tbuckley/cabot-search huggingface dataset:
P163 Tiotropium decreases the risk of exacerbations in patients with symptomatic asthma regardless of baseline characteristics including markers of allergic status
Authors: DMG Halpin, ED Bateman, DP Tashkin, M Engel, R Dahl, P Paggiaro, E Beck, M Vandewalker, W Seibold, P Moroni-Zentgraf, H Schmidt, HAM Kerstjens
Journal: Thorax (2013)

<h3>Rationale</h3> The addition of tiotropium provides bronchodilation and reduces exacerbations in patients with severe asthma (Kerstjens <i>et al</i>. NEJM 2012). Subgroup analyses were performed to determine whether this positive effect was limited to definable subgroups. <h3>Methods</h3> Eligible patients: were aged 18–75 years; had a =5-year history of asthma; were diagnosed before the age of 40; scored =1.5 on Asthma Control Questionnaire 7; and were life-long non-smokers or ex-smokers (&lt;10 pack-years) who quit smoking =1 year before study enrolment. Patients had experienced =1 exacerbation in the previous year. Time to first severe exacerbation from the pooled data after 48 weeks was one of three primary end points. Secondary end points included time to first episode of asthma worsening. Subgroup analyses of time to first severe exacerbation were performed in groups defined by baseline characteristics, including age, allergic status, smoking status and reversibility. <h3>Results</h3> 912 patients were randomised: 456 received 5 µg tiotropium via Respimat<sup>®</sup> Soft Mist™ Inhaler and 456 received placebo once daily for 48 weeks. In the total study group, the time to first severe exacerbation was increased by the addition of tiotropium (risk reduction 21%; hazard ratio 0.79; p = 0.03). The time to first episode of asthma worsening was increased in the tiotropium group compared with placebo (risk reduction 31%; hazard ratio 0.69; p &lt; 0.001). Subgroup analyses showed that neither the time to first severe exacerbation (Figure) nor the time to first episode of asthma worsening was dependent on baseline characteristics (no significant interactions). <h3>Conclusions</h3> The increase in time to first severe exacerbation and first episode of asthma worsening found with the addition of tiotropium was not limited to specific subgroups of patients, including some characteristics that are usually found in patients with chronic obstructive pulmonary disease, such as former smoking, non-allergic status or minimal reversibility. Tiotropium seems effective across a broad spectrum of patients with severe persistent asthma who remain symptomatic and experience exacerbations despite the combination use of moderate- to high-dose inhaled corticosteroids plus long-acting beta agonists.
IMMUNOLOGICAL STUDIES WITH THE VIRUS OF INFECTIOUS LARYNGOTRACHEITIS OF FOWLS USING THE DEVELOPING EGG TECHNIQUE
Authors: F. M. Burnet
Journal: The Journal of Experimental Medicine (1936)

(1) The technique of chorioallantoic membrane inoculation has been applied to the study of the virus of infectious laryngotracheitis as it occurs amongst Australian poultry. (2) When suitably diluted suspensions of virus are inoculated, isolated foci or pocks appear whose macroscopic form and histological structure is characteristic. The numbers of these foci may be used as a measure of the amount of virus present. (3) Two distinct types of focus are produced by laryngotracheitis strains, one being characteristic of epizootic strains from New South Wales and from America, the other of a Victorian strain which is of very low virulence for fowls. (4) No qualitative antigenic differences can be detected amongst these strains but the epizootic strains are more readily neutralised by immune serum than the enzootic Victorian strain. (5) A study of the inactivation of the virus by immune serum shows that (a) the process of inactivation requires time for its completion in vitro; (b) the proportionate reduction in titre produced by a given concentration of antiserum is independent of the initial virus concentration; (c) reactivation by dilution is readily demonstrable; (d) virus in the presence of small concentrations of immune serum producing only a slight inactivating effect is rendered incapable of passing a gradocol membrane normally permeable to it; (e) the foci produced from partially neutralised virus suspensions are smaller than normal, suggesting delay in the initiation of foci. (6) These findings bring the neutralisation of a typical virus by immune serum completely into line with the phage-antiphage reaction as described by Andrewes and Elford.
Screening for lung cancer: yet another problem
Authors: S. G Spiro
Journal: Thorax (2007)

Implementation of a mass screening programme for lung cancer

Lung cancers present late, allowing most sufferers little chance of curative treatment. Presenting symptoms are usually non-specific and give the primary-care physicians little to look out for to separate the presentation of lung cancer, which is the most serious of diseases, from the common cold, a respiratory tract infection, fibromyalgia or any other self-limiting condition of little long-term consequence that he or she sees in daily abundance.1 It has been known for years however, that the most favourable presentation for lung cancer is the chance discovery on a routine chest radiograph, and this was one of the drivers for the chest radiograph to be used as a screening tool for lung cancer in the 1950s and 1960s. However, although chest radigraph screening studies, where usually individuals are randomised to an x ray annual screen or simple follow-up, did disclose more cancers in the active study arm, their mortality was not improved.2–4 These studies have been criticised for several reasons, including inadequate number of entrants, non-compliance in the follow-up only arm and claims that, maybe after all, there was a potential advantage in mortality for the screen-discovered cancers. Nevertheless, the issue was dropped until the development of low-dose multi-slice computed tomography scanning made computed tomography suitable for studying large numbers of people with only a small radiation exposure. Over the past 10 years, there have been several hypothesis-generating studies on populations with differing degrees of risk for developing lung cancer who have undergone prevalence and incidence computed tomography screening in non-randomised studies. These studies have been carried out mainly in Japan and the United States, and have incorporated healthy volunteers of middle or late age (45 years or more), of sufficient health status to be likely to live for …
Inhibition of PAF-induced expression of CD11b and shedding of L-selectin on human neutrophils and eosinophils by the type IV selective PDE inhibitor, rolipram
Authors: C Berends, B Dijkhuizen, JG de Monchy, AE Dubois, J Gerritsen, HF Kauffman
Journal: European Respiratory Journal (1997)

We quantitatively determined whether the selective phosphodiesterase (PDE) inhibitor, rolipram, inhibits changes in the adhesion molecules CD11b and L-selectin on platelet-activating factor (PAF)-stimulated human neutrophils and eosinophils in vitro. Incubations were performed in human whole blood obtained from healthy volunteers, to restrict activation by purification procedures and to simulate in vivo conditions, in which different cell types may interact, more closely. Receptor expression was measured after fixation of cells, using monoclonal antibodies and flow cytometry. Concentration-dependent inhibition of the PAF-induced CD11b expression and L-selectin shedding for neutrophils and eosinophils was observed with rolipram, dibutyryl cyclic adenosine monophosphate (cAMP), prostaglandin E2 (PGE2), and isoproterenol. However, these inhibitions did not exceed 50%. Preincubation with rolipram (10(-8) M) and subsequent incubation with isoproterenol (0.5x10(-8) M) or PGE2 (10(-8) M) induced a cumulative, but not synergistic, effect. Using the combination of rolipram with isoproterenol or PGE2, inhibition of PAF-induced L-selectin shedding from eosinophils was as high as 71+/-28 and 67+/-21%, respectively. Other inhibitions were below 50%. In conclusion, rolipram inhibits CD11b expression and L-selectin shedding of platelet-activating factor-stimulated neutrophils and eosinophils in whole blood in a concentration-dependent fashion. Inhibitions did not exceed 50%, even at high concentrations. The inhibition of platelet-activating factor induced shedding of L-selectin from eosinophils with a combination of rolipram and prostaglandin E2 or isoproterenol, however, was found to be approximately 70%. Inhibition of rolling adhesion of eosinophils may, therefore, be a mode of action of type IV phosphodiesterase inhibitors.
Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim inchemotherapy-induced neutropenia: a multicenterdose-finding study in women with breast cancer
Authors: F.A. Holmes, S.E. Jones, J. O’Shaughnessy, S. Vukelja, T. George, M. Savin, D. Richards, J. Glaspy, L. Meza, G. Cohen, M. Dhami, D.R. Budman, J. Hackett, M. Brassard, B.B. Yang, B.C. Liang
Journal: Annals of Oncology (2002)
A Sensitive Double-Isotope Derivative Assay for Norepinephrine and Epinephrine
Authors: KARL ENGELMAN, BARRY PORTNOY, NANCY HURLEY
Journal: Circulation Research (1970)

A sensitive and specific double-isotope dilution method for assaying norepinephrine and epinephrine separately is described. The method is based on enzymatic conversion of these two catecholamines to their respective metanephrines and was applied successfully to measurement of resting plasma concentrations of norepinephrine and epinephrine in normal subjects with the finding that norepinephrine (0.20 ± 0.08 µg/liter) normally constitutes approximately 80% of the plasma catecholamine content and epinephrine (0.05 ± 0.03 µg/liter) 20%.
Inhalation of swine dust induces cytokine release in the upper and lower airways
Authors: Z Wang, K Larsson, L Palmberg, P Malmberg, P Larsson, L Larsson
Journal: European Respiratory Journal (1997)

In healthy subjects, acute inhalation of swine dust causes an influx of inflammatory cells into the airways and increased bronchial responsiveness. The exposure may also cause fever and generalized symptoms. It seems likely that proinflammatory cytokines are involved in the response to inhaled swine dust. Nasal and bronchoalveolar lavage (BAL) were performed before, and 7 and 24 h after the start of 3 h exposure to swine dust, during a period of work in a swine confinement building, in 22 healthy subjects. Lavage fluids were analysed with regard to the cellular response and concentrations of interleukin (IL)-1 alpha, IL-1 beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Each subject carried personal samplers for exposure measurements. Inhalable dust and airborne endotoxin, 3-hydroxylated (2-OH) fatty acid and muramic acid were measured. Bronchial responsiveness to methacholine was investigated 1-2 weeks before and 7 h after the start of the exposure. Exposure caused fever (&gt; 38 degrees C) in three subjects, and approximately 25% of the subjects experienced symptoms. Bronchial responsiveness to methacholine increased by 3.5 (1.6-4.8) doubling doses (median (25th-75th percentile)). Following exposure, granulocytes increased more than 50 fold in BAL fluid and more than 40 fold in nasal lavage fluid. IL-1 alpha and IL-1 beta increased significantly in BAL fluid (p &lt; 0.05) and nasal lavage fluid (p &lt; 0.01). IL-6 increased 25 fold in BAL and 15 fold in nasal lavage fluid (p &lt; 0.001). TNF-alpha was below detection limit (0.25 ng.L-1) in most subjects before exposure and increased following exposure to 3.8 (2.4-5.7) and 1.3 (0.6-2.3) ng.L-1 in BAL and nasal lavage fluid, respectively, (p &lt; 0.001). Total inhalable dust was 20.5 (14.6-30.0) mg.m-3 and the concentrations of airborne endotoxin, 3-OH fatty acid and muramic acid were 1.2 (0.8-1.4), 3.5 (2.2-4.5) and 0.9 (0.3-1.9) microgram.m-3, respectively. There was a significant correlation between the IL-6 response in BAL fluid and exposure to dust endotoxin activity and 3-OH fatty acids (p &lt; 0.05). Otherwise, no significant correlations were found between exposure and the cytokine response. We conclude that exposure to swine dust causes an intense upper and lower airway inflammation, which involves the proinflammatory cytokines interleukin-1, interleukin-6 and tumour necrosis factor-alpha.
Transformation of Mental Health Care for U.S. Soldiers and Families During the Iraq and Afghanistan Wars: Where Science and Politics Intersect
Authors: Charles W. Hoge, Christopher G. Ivany, Edward A. Brusher, Millard D. Brown, John C. Shero, Amy B. Adler, Christopher H. Warner, David T. Orman
Journal: American Journal of Psychiatry (2015)

The cumulative strain of 14 years of war on service members, veterans, and their families, together with continuing global threats and the unique stresses of military service, are likely to be felt for years to come. Scientific as well as political factors have influenced how the military has addressed the mental health needs resulting from these wars. Two important differences between mental health care delivered during the Iraq and Afghanistan wars and previous wars are the degree to which research has directly informed care and the consolidated management of services. The U.S. Army Medical Command implemented programmatic changes to ensure delivery of high-quality standardized mental health services, including centralized workload management; consolidation of psychiatry, psychology, psychiatric nursing, and social work services under integrated behavioral health departments; creation of satellite mental health clinics embedded within brigade work areas; incorporation of mental health providers into primary care; routine mental health screening throughout soldiers’ careers; standardization of clinical outcome measures; and improved services for family members. This transformation has been accompanied by reduction in psychiatric hospitalizations and improved continuity of care. Challenges remain, however, including continued underutilization of services by those most in need, problems with treatment of substance use disorders, overuse of opioid medications, concerns with the structure of care for chronic postdeployment (including postconcussion) symptoms, and ongoing questions concerning the causes of historically high suicide rates, efficacy of resilience training initiatives, and research priorities. It is critical to ensure that remaining gaps are addressed and that knowledge gained during these wars is retained and further evolved.
erbB-2 and Response to Doxorubicin in Patients With Axillary Lymph Node-Positive, Hormone Receptor- Negative Breast Cancer
Authors: Soonmyung Paik, John Bryant, Chanheun Park, Bernard Fisher, Elizabeth Tan-Chiu, David Hyams, Edwin R. Fisher, Marc E. Lippman, D. Lawrence Wickerham, Norman Wolmark
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin. A retrospective study was designed to test this hypothesis. Methods: In National Surgical Adjuvant Breast and Bowel Project protocol B-11, patients with axillary lymph node-positive, hormone receptor-negative breast cancer were randomly assigned to receive either Lphenylalanine mustard plus 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF). Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients. Statistical analyses were performed to test for interaction between treatment and erbB-2 status (Positive versus negative) with respect to disease-free survival (DFS), survival, recurrence-free survival (RFS), and distant diseasefree survival (DDFS). Reported P values are two-sided. Results: Overexpression of erbB-2 (i.e., positive immunohistochemical staining) was observed in 239 (37.5%) of the 638 tumors studied. Overexpression was associated with tumor size (P = .02), lack of estrogen receptors (P = .008), and the number of positive lymph nodes (P = .0001). After a mean time on study of 13.5 years, the clinical benefit from doxorubicin (PAF versus PF) was statistically significant for patients with erbB-2-positive tumors—DFS: relative risk of failure (RR) = 0.60 (95% confidence interval [CI] = 0.44- 0.83), P = .001; survival: RR = 0.66 (95% CI = 0.47-0.92), P = .01; RFS: RR = 0.58 (95% CI = 0.42-0.82), P = .002; DDFS: RR = 0.61 (95% CI = 0.44-0.85), P = .003. However, it was not significant for patients with erbB-2-negative tumors— DFS: RR = 0.96 (95% CI = 0.75-1.23), P = .74; survival: RR = 0.90 (95% CI = 0.69-1.19), P = .47; RFS: RR = 0.88 (95% CI = 0.67-1.16), P = .37; DDFS: RR = 1.03 (95% CI = 0.79- 1.35), P = .84. Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS (P = .02) and DDFS (P = .02) but not for survival (P = .15) or RFS (P = .06). Conclusions: These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer. [J Natl Cancer Inst 1998;90:1361-70]
High-Grade Glioma Formation Results from Postnatal Pten Loss or Mutant Epidermal Growth Factor Receptor Expression in a Transgenic Mouse Glioma Model
Authors: Qingxia Wei, Laura Clarke, Danielle K. Scheidenhelm, Baoping Qian, Amanda Tong, Nesrin Sabha, Zia Karim, Nicholas A. Bock, Robert Reti, Rolf Swoboda, Enkhtsetseg Purev, Jean-Francois Lavoie, M. Livia Bajenaru, Patrick Shannon, Dorothee Herlyn, David Kaplan, R. Mark Henkelman, David H. Gutmann, Abhijit Guha
Journal: Cancer Research (2006)

Abstract High-grade gliomas are devastating brain tumors associated with a mean survival of &amp;lt;50 weeks. Two of the most common genetic changes observed in these tumors are overexpression/mutation of the epidermal growth factor receptor (EGFR) vIII and loss of PTEN/MMAC1 expression. To determine whether somatically acquired EGFRvIII expression or Pten loss accelerates high-grade glioma development, we used a previously characterized RasB8 glioma-prone mouse strain, in which these specific genetic changes were focally introduced at 4 weeks of age. We show that both postnatal EGFRvIII expression and Pten inactivation in RasB8 mice potentiate high-grade glioma development. Moreover, we observe a concordant loss of Pten and EGFR overexpression in nearly all high-grade gliomas induced by either EGFRvIII introduction or Pten inactivation. This novel preclinical model of high-grade glioma will be useful in evaluating brain tumor therapies targeted to the pathways specifically dysregulated by EGFR expression or Pten loss. (Cancer Res 2006; 66(15): 7429-37)
<i>De novo</i> Identification of <i>MIZ-1</i> (<i>ZBTB17</i>) Encoding a MYC-Interacting Zinc-Finger Protein as a New Favorable Neuroblastoma Gene
Authors: Naohiko Ikegaki, Takahiro Gotoh, Bing Kung, Justin S. Riceberg, David Y. Kim, Huaqing Zhao, Eric F. Rappaport, Sakeenah L. Hicks, Robert C. Seeger, Xao X. Tang
Journal: Clinical Cancer Research (2007)

Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. Favorable neuroblastoma genes (EPHB6, EFNB2, EFNB3, NTRK1, and CD44) are genes whose high-level expression predicts favorable neuroblastoma disease outcome. Accordingly, the forced expression of these genes or their reactivation by gene silencing inhibitors in unfavorable neuroblastoma cells results in suppression of tumor growth and metastases. This study was undertaken to design an experimental strategy to identify additional favorable neuroblastoma genes.Favorable neuroblastoma gene candidates were first identified by gene expression profiling analysis on IMR5 neuroblastoma cells treated with inhibitors of DNA methylation and histone deacetylase against the untreated control cells. Among the candidates, we focused on MIZ-1, which encodes a MYC-interacting zinc-finger protein, because it is known to enhance the expression of growth suppressive genes, such as CDKN1A.High-level MIZ-1 expression was associated with favorable disease outcome of neuroblastoma (P = 0.0048). Forced MIZ-1 expression suppressed in vitro growth of neuroblastoma cell lines. High MIZ-1 expression was correlated with the small-size neuroblastoma xenografts treated with gene silencing inhibitors or a glucocorticoid. In addition, forced MIZ-1 expression enhanced the expression of CD44 and EFNB2 in neuroblastoma cell lines in vitro. Furthermore, MIZ-1 expression was positively correlated with the expression of favorable neuroblastoma genes (EFNB2, EFNB3, EPHB6, and NTRK1) in the human neuroblastoma xenograft therapeutic models.MIZ-1 is a new favorable neuroblastoma gene, which may directly or indirectly regulate the expression of other favorable neuroblastoma genes.
MOLECULAR GENETIC ANALYSIS OF SYNAPTIC PLASTICITY, ACTIVITY-DEPENDENT NEURAL DEVELOPMENT, LEARNING, AND MEMORY IN THE MAMMALIAN BRAIN
Authors: Chong Chen, Susumu Tonegawa
Journal: Annual Review of Neuroscience (1997)

▪ Abstract Recently, dozens of mutant mice generated with gene targeting or transgenic technologies have been shown to exhibit a distinct set of impairments in the brain and behavior. In this review, we discuss how studies of mutant mice have helped elucidate the mechanisms that underlie synaptic plasticity and the relationship of these synaptic mechanisms to the activity-dependent phase of neural development and learning and memory. We focus on the recent progress in the analysis of whisker-related pattern formation, elimination of climbing fibers, long-term potentiation, long-term depression, and various learning and memory tasks in mutant mice.
Phylogeography and pleistocene evolution in the North American black bear
Authors: S Wooding, R Ward
Journal: Molecular Biology and Evolution (1997)

To determine the extent of phylogeographic structuring in North American black bear (Ursus americanus) populations, we examined mitochondrial DNA sequences (n = 118) and restriction fragment length polymorphism profiles (n = 258) in individuals from 16 localities. Among the bears examined, 19 lineages falling into two highly divergent clades were identified. The clades differ at 5.0% of nucleotide positions, a distance consistent with an origin 1.8 MYA, and have different but overlapping geographical distributions. Areas of clade cooccurrence show that eastern and western populations are currently mixing, but regional differences in lineage distribution suggest that mixing has begun only recently. The long-term population history of black bears appears to be characterized predominantly by long-term regional isolation followed by recent contact and hybridization. Congruence between the pattern of diversity observed in black bears and patterns of forest refuge formation during the Pleistocene supports earlier speculation that Pleistocene forest fragmentations underlie a common pattern in the phylogeography of North American forest taxa.