tbuckley/cabot-search huggingface dataset:
Preliminary study to evidence potential adult pulmonary stem cells on endoscopic transbronchial biopsy
Authors: Mario Santagiuliana, Davide Confalonieri, Serena Bonin, Caterina Antonaglia, Marco Confalonieri
Journal: European Respiratory Journal (2013)

Background   Experimental investigations detected the existence of pulmonary stem cell niches with renewal, clonogenicity and multipotential proprieties, both in vitro and in vivo, localized on distal airways. Kumar et al. reported that p63+ basal cells of distal airways act as adult stem cells in murine models of ARDS due to H1N1 infection. After damage these cells radiate to interbronchiolar regions, assembling into Krt5+ pods and initiating expression of alveoli markers. The identification of these human cells could be obtained by surgery specimens or more easily by bronchoscopic procedures.   Objectives   Investigate the presence of putative pulmonary adult stem cells (p63+ and Krt5+) in patients with different lung diseases using a minimally invasive and repeatable technique, the transbronchial biopsy (TBB) obtained during usual fiberoptic bronchoscopy.   Methods   31 TBBs from patients with different lung diseases (18 lung cancers, 5 lung lymphomas, 4 interstitial lung diseases, 2 lung metastasis, 1 mediastinal adenopathy, 1 lung infection) were selected and processed to immunohistochemistry (IHC) using  Lung squamous 2™  ( Bicare Medical, Concord, CA, USA ).   Results   14 out of 31 samples were suitable for IHC analysis. 4 samples (12,9%) showed p63+ and Krt5+ cells, two of these (6,5%) presented presumed stem cells niches in patients with MALT lymphoma and undifferentiated squamous cells carcinoma.   Conclusions   We identified potential stem cell niches in a few TBBs. Nowadays TBBs don9t seem suitable for investigation of potential adult stem cells in lung tissues. We recognize that the limitation of our study is the sample size and to confirm our results a larger case study should be analyzed.
Alveolar lymphocytes (AL) produce interleukin 27 (IL27), antigen presenting cell-secreted cytokine. Increased expression of IL27 in bronchoalveolar lavage (BAL) of pulmonary sarcoidosis (PS) patients
Authors: Tomasz Wandtke, Joanna Chorostowska-Wynimko, Adam Szpechcinski, Grzegorz Przybylski, Agnieszka Jarzemska, Ewelina Wedrowska, Agata Gizycka, Joanna Wielikdzien, Piotr Kopinski
Journal: European Respiratory Journal (2013)

Introduction:  IL27, a cytokine produced by antigen presenting cells (APCs) is one of the early factors driving Th1 polarization of lymphocytes. In spite of numerous studies, it seems the present knowledge about IL27 expression in lower airways is still deficient.   Aim:  To determine sources of IL27 in human lower airways in BAL in interstitial lung diseases (ILD) patients.   Materials and Methods:  The local sources of IL27 were determined in BAL cells by indirect phenotyping and flow cytometry. IL27 concentration in BAL supernatants was examined by ELISA. Cells and supernatants were collected from patients with PS (n=13, 3 steroid treated subjects), idiopathic pulmonary fibrosis (IPF, n=3), nonspecific interstitial pneumonia (NSIP, n=5), exogenous allergic alveolitis (EAA, n=3) and controls (n=3).   Results:  Alveolar macrophages were proved positive for intracellular IL27 expression. The IL27 intracellular staining proved positive also for AL in almost all ILD patients (n=22) and in controls (n=3). IL27+ AL were detected in BAL material from PS (n=10, 89±15.5, 49-100%; all results as median±SEM, range), EAA (21±8.7, 11-23%) and NSIP (75±6.5, 54-85%) patients and in controls (46±15.0, 7-85%). IL27 was also detected in BAL supernatants by ELISA in 6 out of 10 steroid-naive PS patients (4.46±1.83, 0-15.49 pg/ml).   Conclusions:  We provided strong preliminary data suggesting IL27 expression by AL and propose that IL27 is secreted in lower airways not exclusively by APCs. Its increased expression in PS suggests IL27 to play a role in ILD pathophysiology, probably as Th1 activity marker.
Chloroquine as a potential adjunctive therapy in tuberculosis
Authors: Ulrich Matt, Rita Müller, Daniel Müller, Albrecht Stenziger, Annelies Zinkernagel, Anna Seelig, Johannes Nemeth
Journal: European Respiratory Journal (2014)

The rise of multi-drug resistant tuberculosis is a major threat. Multi drug efflux pumps are believed to significantly contribute to the development of resistance by reducing the intracellular concentration of the standard therapy, consisting of isoniazid (INH), ethambutol (ETH), rifampicin (RIF) and pyrazinamid (PZA). Immunohistochemical staining from a patient with tuberculosis of the lymphnodes revealed significant expression of P-gp and BCRP in macrophages at the site of infection. Next, we screened the interaction of tuberculostatics with P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein-1 (BCRP, ABCG2) over-expressed in plasma membranes using an ATPase activity assay. INH and PZA were found to be substrates for BCRP, substantially increasing its activity at clinical concentrations. Moreover, the antimalarial chloroquine inhibited both pumps at clinically relevant concentrations. Differentiated THP-1macropaghes were shown to significantly increase the expression of the respective pumps upon stimulation with interferon (IFN)-γ. In a functional assay, the efflux of INH was reduced in the presence of therapeutic concentrations of chloroquine, as measured in the supernatant with liquid chromatography–high resolution mass spectrometry. This effect was clearly more pronounced in IFN-γ stimulated macrophages. In conclusion, we showed for the first time that INH and PZA are substrates for BCRP. IFN-γ stimulated cells pumped INH out into the extracellular space, an effect which could be reversed by chloroquine. Altogether chloroquine, a safe and well-tolerated drug with a long half-life could enhance intracellular tuberculostatic activity, potentially shortening treatment duration.
Ondansetron versus ondansetron, dexamethasone, and chlorpromazine in the prevention of nausea and vomiting associated with multiple-day cisplatin chemotherapy.
Authors: S M Fox, L H Einhorn, E Cox, N Powell, A Abdy
Journal: Journal of Clinical Oncology (1993)

PURPOSE This study is designed to evaluate the effectiveness of ondansetron alone (OND) or in combination with 2 days of dexamethasone and 5 days of chlorpromazine (ODC) in the prevention of emetic episodes in patients receiving multiple-day cisplatin. PATIENTS AND METHODS Forty-four patients receiving 20 or 40 mg/m2 of cisplatin daily for 4 to 5 days plus etoposide (VP-16) alone or in combination with bleomycin or ifosfamide were randomized to receive three doses of OND (0.15 mg/kg 30 minutes before and 4 and 8 hours after cisplatin) versus the identical OND regimen plus dexamethasone 8 mg before cisplatin and 4 mg 4 and 8 hours later on days 1 and 2, plus chlorpromazine 50 mg every 4 hours for four doses per day. Patients were chemotherapy-naive, had a Karnofsky performance status &gt; or = 60, and were not receiving nonstudy antiemetics. RESULTS Nineteen of 22 patients (86%) on ODC had fewer than three emetic episodes throughout the study period, compared with 10 of 22 (46%) on OND (P = .009), and 55% of patients on ODC had no emetic episodes, compared with 32% on OND (P = .22). The ODC arm had fewer treatment failures (5%) than the OND arm (32%). The mean nausea ratings per visual analog scale were 15.0 for OND and 5.5 for ODC (P = .046). Headache was less frequent with ODC versus OND (14% and 41%, respectively, P = .09). CONCLUSION ODC was superior to OND with respect to therapeutic efficacy and decreased headaches. Both OND and ODC were more effective on days 1 and 2, rather than days 4 and 5, suggesting tachyphylaxis, anticipatory nausea, or delayed nausea from the first few days of cisplatin combination chemotherapy.
Hyperoxia impairs the inflammatory response of alveolar macrophages to multiple Toll-like receptor ligands associated with bacterial infection
Authors: Hideaki Yamasawa, Naoko Mato, Masashi Bando, Yukihiko Sugiyama
Journal: European Respiratory Journal (2014)

Introduction:  Oxygen therapy is a necessary component of the treatment provided to patients with acute respiratory failure. However, little is known about the impact of  in vivo  hyperoxia on pulmonary host defenses.  Aim:  Alveolar macrophages (AMs) constitute the first-line defense against inhaled pathogens. We investigated the effect of hyperoxia on Toll-like receptor (TLR)-mediated proinflammatory cytokine production by AMs.  Methods:  C57BL/6 mice were exposed to 80-90% oxygen for 96 h. AMs obtained from control mice and hyperoxia-exposed mice were stimulated  ex vivo  with the following: a TLR2 ligand, Pam3CSK4 (Pam3); a TLR4 ligand, lipopolysaccharide (LPS); a TLR5 ligand, flagellin (FLG); or a TLR3 ligand, poly I:C (PIC).  Results:  AMs from the hyperoxia-exposed mice produced significantly less TNF-α and IL-6 after Pam3, LPS, or FLG stimulation compared with AMs from the control mice. The decreased production of these cytokines was associated with reduced mRNA expression of the corresponding cytokines. Both cell surface and mRNA expression of TLR2, 4, and 5 in the AMs were significantly decreased following  in vivo  hyperoxia. In contrast, production of TNF-α after PIC stimulation did not differ between the two groups of AMs. Production of RANTES was decreased in AMs from hyperoxia-exposed mice after LPS, but not PIC, stimulation. No differences were observed in TLR3 mRNA expression in AMs between the control and hyperoxia-exposed mice.  Conclusion:  Hyperoxia impairs the reactivity of AMs to multiple TLR ligands typically associated with bacterial infection. This effect might result from a hyperoxia-induced decrease in TLR expression.
Platelet Activating Factor in Endotoxin and Immune Diseases
Journal: Thorax (1990)

of the New Zealand Department of Health's recommendations advising against the use of fenoterol in patients with severe asthma, Duovent was deleted from the protocol and ipratropium bromide (Atrovent) is available when a further nebulised bronchodilator is required.We acknowledge Drs P Rothwell and B Mahood for suggesting the use of such protocols, Dr H Leslie and the staff of the Wellington Hospital emergency department for their interest and cooperation, and the secretarial staff of the department of medicine.
Anti-remodeling potencies of the soluble guanylate cyclase activator BAY 41-2272 in human lung fibroblasts
Authors: Christopher Lambers, Michael Roth, Elisabeth Hofbauer, Venzel Petkov, Lutz-Henning Block
Journal: European Respiratory Journal (2014)

Idiopathic pulmonary fibrosis (IPF) is typically a disease of the elderly and associated with poor prognosis. The hallmark of IPF is a diffuse tissue remodeling which results in major structural changes including mesenchymal cell hyperplasia and increased interstitial extracellular matrix (ECM) deposition mainly mediated by transforming growth factor (TGF) beta. Current evidence suggests important roles for local proliferation and differentiation of resident fibroblasts.  We investigated the effect of the soluble Guanylate Cyclase (sGC) activator BAY 412272 on TGF induced ECM gene transcription and proliferation.  Human lung fibroblasts were treated with TGF-beta (+/-) BAY 41 2272, Forskolin (FSK) and vehicle. mRNA transcription was measured by RT-PCR for Collagen type 1 (COL1), Fibronectin (FN), alpha smooth muscle actin (aSMA) and beta-Catenin. Proliferation was measured by cell count. All experiments were performed in triplicates.  Stimulation of the cells with TGF led to a significant increase of mRNA transcription of Fibronectin (6.1 fold), Collagen type I (12.3 fold), a-SMA (3.9 fold;) and Catenin (3.6 fold), while pre-treatment with BAY 41-2272 resulted in a dose dependent significant reduction for COL1, FN, Catenin and a-SMA.  TGF significantly increased cell proliferation after 72 hours. In contrast, the addition of BAY 41-2272 reversed this effect completely.  These findings suggest that TGF driven ECM composition and cell proliferation can be modified by activation of soluble Guanylyl Cyclase (sGC). The demonstrated pharmacological effect of BAY 41-2272 proposes a new mode of action of the compound to prevent pulmonary remodeling.
Exhaled nitric oxide and clinical phenotype of childhood asthma
Authors: Bruno Mahut, Séverine Peyrard, Christophe Delclaux
Journal: European Respiratory Journal (2011)

Question. To evaluate whether exhaled NO (FENO0.05) is associated with pathophysiological characteristics such as airway tone (bronchodilator response) and inflammation (inhaled corticosteroid [ICS]-dependent inflammation), and with phenotypes of childhood asthma.   Methods:  We performed multivariate and k-means cluster analyses in a population of 169 asthmatic children (age ± SD: 10.5±2.6 years) recruited in a cohort characterized in a cross-sectional design using 28 parameters of different domains: atopy, environment (tobacco), control, exacerbations, treatment (ICS and long-acting bronchodilator agonist), and lung function (airway architecture and tone).   Results:  Two subject-related (height and atopy) and two disease-related characteristics (bronchodilator response and ICS dose>200 μg/d) explained 36% of exhaled NO variance. Principal component analysis isolated 9 domains and 4 clusters were identified: 1 (47%): boys, unexposed to tobacco, with well-controlled asthma; 2 (26%): girls, unexposed to tobacco, with well-controlled asthma; 3 (6%): girls or boys, unexposed to tobacco, with uncontrolled asthma and increased tone, and 4 (21%): girls or boys, exposed to parental smoking, with small airway to lung size ratio and uncontrolled asthma. Importantly, FENO0.05 was not different in these four clusters.   Conclusion:  Despite its relationships with pathophysiological characteristics, FENO0.05 does not help to identify a relevant phenotype of asthmatic children.
Association between antimicrobial household products exposure and allergic symptoms in Korean children
Authors: Wan-ryung Lim, Soyoung Hong, Hojang Kwon, Won-Jun Choi, Hyunjung Kim, Chaebong Kim, Jeonghoon Kim, HeaSuk Yang, KyooSang Kim
Journal: European Respiratory Journal (2013)

Antimicrobial chemicals are used in variety of household and personal care products. Exposure to antimicrobial chemicals has been hypothesized to lead to allergic diseases. We investigated antimicrobial household product exposure and allergic diseases in Korean children.  A total of 35,590 children in Seoul, the capital of South Korea, participated in this cross-sectional study. An antimicrobial exposure (AE) score was derived (0 for not at all, 1 for less than once per week, 2 for approximately once per week, 3 for most days, and 4 for every day). To examine the symptoms of allergic diseases (current wheeze, current rhinitis, and current eczema) in the past 12 months, a questionnaire based on the International Study of Asthma and Allergies in Children (ISAAC) core module was used. Complete data for the analysis were available for 25,805 of the 35,590 (72.5%) children.  The prevalence of current allergic diseases was as follows: wheeze in 5.6%, allergic rhinitis in 32.6%, and eczema in 17.7%. The mean (standard deviation [SD]) AE score was 14.3 (9.3) (range: 0-40). Compared with subjects with a low AE score (reference), subjects with a high AE score (fourth quartile) were more likely to have symptoms of wheezing and allergic rhinitis (adjusted odds ratio (OR) for wheezing 1.24, 95% confidence interval (CI) 1.05-1.45, p for trend = 0.24; adjusted OR for allergic rhinitis 1.30, 95% CI 1.20-1.40, p
Obstructive sleep apnea syndrome (OSAS) and asthma in a general Norwegian population
Authors: Trygve Jonassen, Tomas Eagan, Sverre Lehmann
Journal: European Respiratory Journal (2011)

Background:  Several studies have investigated associations between OSAS and asthma, with inconsistent results.   Aim:  To determine if asthma and bronchodilator reactivity (BDR) are independent risk factors for OSA in the Norwegian population.   Methods:  An age and sex stratified random sample of all adults aged 47-48 and 71-73 living in Bergen, Norway, were invited to a cross-sectional survey. The 3506 attendants (69%) completed a questionnaire including symptoms of OSAS. Subjects were classified as having OSAS if they reported snoring, breathing cessations, and daytime sleepiness using the Karolinska Sleep Questionnaire, previously validated against polysomnography. Subjects were classified as asthmatics if they had ever received a doctor9s diagnosis of asthma and currently were on antiobstructive medication. Spirometry including bronchodilator test inhaling 400 μg Salbutamol was performed by all subjects. Two logistic regression models were fitted with OSAS as the outcome variable; one with current asthma and one with BDR as main explanatory variable. Both models included age, sex, body mass index (BMI), waist-hip ratio and smoking.   Results:  The prevalence of OSAS was 4,5% (147/3289) in subjects without asthma, and 9,7% (21/217) in subjects with asthma [P=0.001]. Subjects with current asthma had an increased risk for OSA with an OR of 2.2 (1.3, 3.7), after adjustment for all confounders. BDR, measured by difference in ml between pre- and post-bronchodilator spirometry, did not seem to confer increased risk for OSAS; OR 1.0 (0.3, 3.8).   Conclusions:  Our study confirms asthma as an independent risk factor for OSAS. We were not able to demonstrate a relationship between bronchodilator reactivity and OSAS.
Oxaliplatin plus continuous infusion topotecan: First stage of an ongoing phase II study for recurrent ovarian cancer: A New York Cancer Consortium study (#N01-CM62204)
Authors: N. LaNatra, H. Hochster, F. Muggia, S. V. Blank, J. Curtin, D. Fishman, I. E. Shapira, G. L. Goldberg, S. Parise, A. Tiersten
Journal: Journal of Clinical Oncology (2009)

5556 Background: Topoisomerase-1 inhibitors and platinums are active in ovarian cancer. Our prior series described infusional topotecan as less myelosuppressive than bolus and more easily combined with oxaliplatin than cisplatin. An NYU phase I study of the combination in previously treated ovarian cancer patients (pts) showed promising activity and good tolerability (Hochster H, Gynecol Oncol 2008). Methods: Ovarian cancer pts treated with 1–2 prior regimens (1 platinum/taxane regimen, no topotecan) were treated with oxaliplatin 85 mg/m 2 day 1, 15 and topotecan (0.4 mg/m 2 /day) continuous infusion x 14 days every 4 weeks (wks). Platinum resistant (stratum I = 10) and sensitive (stratum II = 17) pts are included in this two-stage trial (n = 52) to evaluate overall response rate (ORR) and toxicities. Results: From January 2006 to November 2008, 27 pts entered. Median age was 61 (37–79). Fifteen pts had 1 prior regimen and 12 pts had 2. Five pts discontinued before 2 cycles (3 for predefined toxicity, 2 by pt/physician choice). 102 cycles of chemotherapy were given (median 4, [1–6]). Grade 3/4 toxicities included thrombocytopenia (37% grade 3, 19% grade 4), neutropenia (37% grade 3, 11% grade 4), anemia (15% grade 3), neuropathy (7% grade 3), diarrhea (4% grade 3), transaminitis (4% grade 3), and fatigue (7% grade 3). Twenty-one pts had day 15 oxaliplatin held, 10 pts required dose reductions, and 21 pts had treatment delays mainly from thrombocytopenia. No pts had neutropenic fever. Twenty-one pts are now evaluable. Stratum I had 1 complete and no partial responses, 5 pts with stable disease and 2 with progressive disease. Stratum II had 3 complete and 6 partial responses, 4 pts with stable disease and none progressed. Median response duration is 41 wks (17–62); median duration of stable disease is 17 wks (4–70). Conclusions: Excluding thrombocytopenia, tolerance to this regimen confirms phase I results. In pts with creatinine clearances (CrCl) &lt; 60 ml/min, the incidence of grade 3/4 thrombocytopenia was 75% versus 35 % for pts with CrCl &gt; 60 ml/min. Pts with CrCl of 40–60 ml/min will now start topotecan 0.3 mg/m 2 /day x 14 days. Reaching our predefined ORR of at least 30% for stratum II and 20% for stratum I, the second stage of accrual has begun. [Table: see text]
Biological dosimetry in lung cancer (LC) patients treated with fractionated radiotherapy (RT)
Authors: Yury Ragulin, Igor Khvostunov, Larisa Kursova, Natalia Shepel, Dmitry Glazyrin, Igor Gulidov
Journal: European Respiratory Journal (2014)

Background. The dicentric assay in human lymphocytes has proved to be the most challenging method of estimating a radiation dose. But considerable inter-patient differences between cytogenetic yields are usually observed in such studies of cancer pts. The objective of this study was to investigate dose response of chromosomal aberrations in human lymphocytes of LC pts under conditions of non-uniform fractional exposures to high doses of RT with synchronous chemotherapy.  Methods. We collated a group of 17 LC pts with II-IV stages wich received RT (total dose ranged 47.5 to 70 Gy). Blood samples for each pt were taken before treatment, after complete course and during the RT. Blood was cultured for 48 hrs according to IAEA protocol for conventional analysis.  Results. The dose estimation of partial body irradiations of pts was carried out based on Dolphins contaminated Poisson and Lea method using in vitro dose-response curve obtained in this study. Based on cytogenetic measurements of seven pts the average tumor dose after first day of treatment was 0.97 to 4.2 Gy given that physical dose was 2.5 Gy. We have estimated linear regression relationship between cytogenetic and physical doses using free parameter t 0  ranged from 0.25 h to 2 h. The quotient of individual dose estimated by the frequency of aberrations to physical dose after RT was 98% (ranged 41 to 122%).  Conclusions. We have shown that after a multiple fraction exposure the dose heterogeneity can be detected using dicentrics assay. The applied approach using only one free parameter was proposed for estimation of partial body dose in LC pts which is expected to result into an objective estimation of the tumor dose.