tbuckley/cabot-search huggingface dataset:
Clinical and pathophysiological features of asthma phenotypes
Authors: Olga Kharevich, Irina Lapteva, Elena Lapteva, Natalia Shpakouskaya, Marina Dzusmikeyeva, Elena Koroleva
Journal: European Respiratory Journal (2013)

Introduction. The phenotyping of patients with asthma can help to develop the differentiated approach in treatment.

The aim of the study was to identify and characterize distinct asthma phenotypes.

Methods. Hierarchical cluster analyses (Ward's method) was performed to identify asthma phenotypes in 61 patients with asthma (67% females, age 50,6±11,1 yrs). The demographic and functional parameters and inflammatory markers were assessed in the revealed clusters.

Results. Three clusters were identified based on gender, age of onset, atopy status, frequency of exacerbations and functional parameters. Cluster 1 (n=21) consisted of predominantly females with atopic asthma, onset of disease in middle age (median 41 yrs) and normal lung function. Cluster 2 (n=20) included both males and females, who were mostly atopic with onset asthma in young adult age (median 23,5 yrs), impaired lung function and frequent exacerbations. Patients from cluster 3 (n=20) also demonstrated impaired lung function and frequent exacerbations, but were non-atopic and had middle age onset asthma (median 44,5 yrs). The patients from clusters 2 and 3 tended to have more severe disease, irreversible airway obstruction, lower postbronhodilator FEV1 and higher RV/TLC as compared with cluster 1. Level of serum total IgE and sputum eosinophil count were similar in all clusters, but sputum neutrophil count was higher in clusters 2 and 3. Moreover, the level of IL-1β was higher in cluster 3 as compared with cluster 2.

Conclusion. Identified clinical asthma phenotypes have different underlying pathophysiological mechanisms. Further evaluation of prognostic value of asthma phenotypes may contribute to the development of the differentiated approach in treatment.
Sustained Inhibition of HER3 and EGFR Is Necessary to Induce Regression of <i>HER2</i>-Amplified Gastrointestinal Carcinomas
Authors: Simonetta M. Leto, Francesco Sassi, Irene Catalano, Valter Torri, Giorgia Migliardi, Eugenia R. Zanella, Mark Throsby, Andrea Bertotti, Livio Trusolino
Journal: Clinical Cancer Research (2015)

Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities.The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstream transducers was evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversible HER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays.Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was also very effective in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib-or, importantly, monotherapy with afatinib-resulted in overt tumor shrinkage.Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res; 21(24); 5519-31. ©2015 AACR.
Clinical significance of tolerant strains of streptococci in adults with infective endocarditis
Authors: T. Hanslik, C. Hartig, C. Jurand, L. Armand-Lefevre, V. Jubault, E. Rouveix, O. Dubourg, J. Prinseau, A. Baglin, M.H. Nicolas-Chanoine
Journal: Clinical Microbiology and Infection (2003)
Dermal fibroblasts from acute inflamed atopic dermatitis lesions display increased eotaxin/CCL11 responsiveness to interleukin-4 stimulation
Authors: N. Gahr, R. Fölster-Holst, M. Weichenthal, E. Christophers, J.-M. Schröder, J. Bartels
Journal: British Journal of Dermatology (2010)

Background The presence of eosinophils and/or eosinophil‐derived products in the dermis is characteristic for involved skin of patients with atopic dermatitis and contributes to the observed tissue injury. CCL11 is a potent chemoattractant and activator of human eosinophils and interleukin (IL)‐4 is a potent inducer of CCL11 expression in dermal fibroblasts. Objectives As increased fibroblast CCL11 expression may explain eosinophilic infiltration of involved skin areas in atopic dermatitis, we asked whether dermal fibroblasts from atopic patients differ from fibroblasts of healthy individuals in their ability to express CCL11. Methods We compared IL‐4‐induced CCL11 mRNA expression using reverse transcription–polymerase chain reaction from cultured dermal fibroblasts derived from biopsies of chronic lesional and acute lesional atopic skin as well as from skin biopsies derived from normal skin of healthy donors. Results Considerable variability in IL‐4‐induced relative CCL11 mRNA expression was detected in fibroblasts derived from biopsies of different individuals. The lowest median IL‐4 concentration inducing half maximal CCL11 mRNA expression (EC50) was found in fibroblasts derived from acute inflamed atopic lesions. Conclusions Inducibility of CCL11 in dermal fibroblasts upon stimulation with Th2 cytokines explains the tissue eosinophilia observed in the presence of Th2 cytokines and the localization of eosinophils to the dermis. Decreased EC50 values of IL‐4‐induced CCL11 expression in fibroblasts from acute inflamed atopic skin lesions indicates increased IL‐4 responsiveness in these lesions and further substantiates the special role for IL‐4‐induced dermal fibroblast CCL11 expression in acute lesions. Variable CCL11 expression in fibroblasts from different patients with atopic dermatitis indicates heterogeneity of factors determining atopic phenotype in atopic dermatitis.
Characterisation of Yersinia pestis isolates from natural foci of plague in the Republic of Georgia, and their relationship to Y. pestis isolates from other countries
Authors: T. Revazishvili, C. Rajanna, L. Bakanidze, N. Tsertsvadze, P. Imnadze, K. O'Connell, A. Kreger, O.C. Stine, J.G. Morris, A. Sulakvelidze
Journal: Clinical Microbiology and Infection (2008)
Airway Eosinophilia in Children with Severe Asthma
Authors: Christiane Lex, Flavia Ferreira, Angela Zacharasiewicz, Andrew G. Nicholson, Patricia L. Haslam, Nicola M. Wilson, Trevor T. Hansel, Donald N. R. Payne, Andrew Bush
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Children with severe asthma experience persistent symptoms despite maximal conventional treatment. Fraction of exhaled nitric oxide (FeNO) and sputum eosinophils are used as markers of airway inflammation to guide treatment with steroids, but no data are available on how reliable they are in predicting airway eosinophilia assessed bronchoscopically in these children.Objectives: To determine how FeNO and sputum eosinophils predict airway eosinophilia measured in both bronchoalveolar lavage (BAL) and endobronchial biopsy.Methods: Twenty-seven children with moderate to severe persistent asthma attempted measurement of FeNO and sputum eosinophils, followed by bronchoscopy, BAL, and endobronchial biopsy within 24 h.Main Results: Significant correlations were found between eosinophils in sputum and both BAL eosinophils (n = 20, r = 0.45, p = 0.045) and FeNO (n = 23, r = 0.42, p = 0.049). The relationship between FeNO and BAL eosinophils was also significant with a stronger correlation (n = 24, r = 0.54, p = 0.006). The positive predictive value (PPV) for increased sputum eosinophil percentage (> 2.5%) to detect elevated eosinophils in BAL (> 1.19%) was 75%; the negative predictive value (NPV) was 63%. All patients with both increased sputum eosinophils and an elevated FeNO value (> 23 ppb) had elevated eosinophils in BAL (PPV, 100%); the NPV of these two markers was 65%. Eight of nine patients without any sputum eosinophils had normal subepithelial eosinophil numbers (< 1.2%; NPV, 89%). However, the PPV of any sputum eosinophils for increased subepithelial eosinophilia was only 36.4%.Conclusions: There was moderate agreement between both FeNO and sputum eosinophils and BAL eosinophils. There was good NPV, but only poor PPV for these markers for mucosal eosinophilia.
In unexplained recurrent pregnancy loss, daily LMWH did not improve ongoing pregnancy or live birth rates
Authors: Alexander Gallus
Journal: Annals of Internal Medicine (2015)

Source Citation Schleussner E, Kamin G, Seliger G, et al; ETHIG II group. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med. 2015;162:601-9. 25938990
An Audit of the Investigation and Treatment of Folic Acid Deficiency
Authors: Neil Haslam, Christopher S Probert
Journal: Journal of the Royal Society of Medicine (1998)

On the suspicion that folate deficiency was not being thoroughly investigated we conducted a retrospective study of management in a teaching hospital. Notes from 84 consecutive patients with low red cell folates (mean age 69.5 years, range 21-95, M:F 33:51) were reviewed for haemoglobin, mean cell volume, dietary history, alcohol consumption, drug history, relevant medical history, relevant investigations, treatment, repeat measurement of red cell folate and diagnosis of deficiency. In 52 (61.9%, mean age 72.9 years, range 33-95, M:F 21:51) no diagnosis was reached. In only 32 (38.1%, mean age 63.9 years, range 21-89, M:F 12:20) was a definitive diagnosis established: 5 had coeliac disease, 1 had Crohn's disease, 9 had drug-associated deficiency (4 methotrexate, 3 phenytoin, 1 trimethoprim and 1 valproate), 1 had combined variable immunodeficiency and 16 had dietary deficiency. In most cases of folic acid deficiency no attempt was made to establish aetiology. We recommend that younger patients without an obvious cause are investigated initially by dietary assessment and measurement of anti-endomysial antibody and by duodenal biopsy with small-bowel follow-through if clinically indicated.
Effect of &lt;italic&gt;Corynebacterium parvum&lt;/italic&gt; on Tumor Growth in the Central Nervous System of Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Frances K. Conley, Jack S. Remington
Journal: JNCI Journal of the National Cancer Institute (1978)

Experiments were performed to determine the effect of systemic Corynebacterium parvum on resistance to growth and development of tumor in the central nervous system. An ependymoblastoma was injected intracerebrally into C57BL/6J female mice that were untreated or had received iv and/or ip injections of C. parvum at various time intervals prior to and after tumor inoculation. The doses of C. parvum and the time schedules used were known to result in populations of activated macrophages. C. parvum did not confer protection against the intracerebral tumor, as measured by time to death or total survival. Histologic examination of brains from untreated and treated mice at various intervals following injection of tumor did not reveal any differences in cellular response to the brain tumor, and C. parvum did not result in an inflammatory response in the brain, whether or not tumor was present. C. parvum did not affect growth and development of ependymoblastoma injected sc; however, when the tumor was injected ip, inhibition of growth was highly significant in the C. parvum-inoculated animals. Thus the antitumor effect of C. parvum differed significantly depending on route of injection of C. parvum and anatomic location of the tumor. Peritoneal macrophages from C. parvum-inoculated mice were cytostatic to ependymoblastoma target cells in vitro, whereas those from untreated mice were not. These results, along with those in a toxoplasmosis model, suggest that failure of systemic C. parvum administration to produce an inflammatory response in the central nervous system is an important factor in the observed lack of tumor resistance.
Efficacy and Safety of Rituximab Combined with P-Imvp-16/Cbdca for Refractory or Relapsed Aggressive B-Cell Lymphoma
Authors: Takuro Matsumoto, Nobuhiko Nakamura, Yuhei Shibata, Hiroshi Nakamura, Junichi Kitagawa, Nobuhiro Kanemura, Naoe Goto, Takeshi Hara, Hisashi Tsurumi, Hisataka Moriwaki
Journal: Annals of Oncology (2014)
Use of the Likelihood Principle for the Determination of Carcinogenic Activity in Pulmonary Tumor Assays
Authors: James R. Zweifel
Journal: JNCI Journal of the National Cancer Institute (1966)

A complete evaluation of the carcinogenic capacity of suspected tumor-inducing agents is often impractical or impossible. In broad screening programs, for the purpose of discovering active agents, it seems unwise to assume that extensive knowledge concerning the finer details of the mechanisms of all agents will be useful or important. For this reason, compounds are tested at three or four carefully selected concentrations and a conclusion is reached whether a compound is active, inactive, or whether further testing will be necessary. To make such decisions, one would like to combine the information from all dose levels and to infer the behavior of the agent outside the range of the experimental conditions tested. In situations where it is possible to derive an appropriate mathematical model, such analyses become feasible. An attempt has been made to provide such a model for the induction of pulmonary tumors in situations where little is known a priori about either the nature of the response (i.e., carcinogenic, inert, therapeutic) or the form of the dose-response relationship. The model has been used to evaluate activity of 29 compounds tested by Shimkin et al.
Gemcitabine in the Treatment of Refractory Hodgkin’s Disease: Results of a Multicenter Phase II Study
Authors: A. Santoro, H. Bredenfeld, L. Devizzi, H. Tesch, V. Bonfante, S. Viviani, F. Fiedler, H. Soto Parra, C. Benoehr, M. Pacini, G. Bonadonna, V. Diehl
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To explore the use of gemcitabine for the treatment of patients with relapsing or refractory Hodgkin’s disease. PATIENTS AND METHODS: Eligible patients had measurable disease and more than one previous chemotherapy regimen. Patients previously treated with high-dose chemotherapy with autologous bone marrow or peripheral stem-cell support were not included. Gemcitabine, 1,250 mg/m 2 , was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle of therapy. The dosing schedule remained fixed, and any dose of gemcitabine that could not be given on time was omitted. Patients who had not experienced any hematologic or nonhematologic toxicity after one complete cycle of therapy were permitted to have subsequent doses increased by 20%: that is, from 1,250 mg/m 2 to 1,500 mg/m 2 . RESULTS: Of the 23 enrolled patients, 22 were assessable for response; all 23 patients were included in the efficacy analysis. Disease status for two patients (9%) reached a state of complete remission, and seven patients (30%) achieved a partial response, for an overall response rate of 39% (95% confidence interval, 19.7% to 61.5%). The likelihood of achieving a response was not influenced by a patients’ main pretreatment characteristics or by their response to their last prior chemotherapy. The median duration of response was 6.7 months (range, 2 to 33+ months), and the median overall survival time was 10.7 months (range, 4 to 34.7+ months). In general, toxicities were mild; no treatment-related deaths occurred, and only one life-threatening adverse event was reported for this study. CONCLUSION: Gemcitabine was shown to be active in heavily pretreated patients with Hodgkin’s disease, producing a response rate of 39%. Additionally, drug-related toxicities were mild, which thus suggests the possible inclusion of gemcitabine in an earlier phase of treatment.
Developmental profile of cellular pathways regulating protein breakdown in the fetal and postnatal diaphragm
Authors: Yong Song, Jane Pillow
Journal: European Respiratory Journal (2011)

Studies on diaphragm weakness and atrophy focus on adult muscle, but the preterm diaphragm might be more susceptible to injury. Characterization of the ontogeny of protein degradation pathways responsible for muscle atrophy would help further understanding of the altered signaling pathways under pathologic conditions in preterm babies. Here, we performed the baseline study of major proteolytic pathways and antioxidant capacity in lambs from 75 d to 200 d postconceptual age. The diaphragm tissues were collected and analysed for gene expression and/or protein abundance in a set of key pathway components in conjunction with proteolysis/antioxidant activity. Our results showed that calpain and caspase 3 in gene and protein expressions exhibited a similar profile with advancing gestation, increasing from 75 d to 100 d/128 d and subsequently decreasing gradually toward full term. In contrast, ubiquitin conjugating and ligase genes did not change during gestation. All proteolytic genes examined (except Ubiquitin) were up-regulated rapidly after delivery, with a similar developmental trend observed in protease activities. Unlike proteolytic pathway pattern, antioxidant gene expression demonstrated a steady increase from 75 d gestation until 24 h after birth, followed by a significant reduction at 7 w of postnatal age (p ≤ 0.002). The proteolytic signaling and antioxidant capacity patterns reflected the adaptive process to metabolic change and muscle maturity with development. The data from this study may partly explain the susceptibility of preterm infants to respiratory failure in response to injurious ventilation and/or clinical stressors such as inflammation and hypoxia.
Determinants of asthma control and quality of life in stable asthma
Authors: Minna Purokivi, Heikki Koskela, Kirsi Kontra
Journal: European Respiratory Journal (2012)

Asthma control and quality of life are poorly associated with traditional asthma biomarkers. In the present study we evaluated two new cough provocation tests in this respect.

Asthma Control Questionnaire and Leicester Cough Questionnaire were completed by thirty-six stable asthmatics. Cough provocation tests with hypertonic saline (Koskela HO et al. Clin Exp Allergy. 2008 Jul;38(7):1100-7) and isocapnic hyperpnoea of dry air were performed (Purokivi M, et al. Cough. 2011;7(1):8), as well as spirometry, ambulatory peak expiratory flow (PEF) monitoring, and exhaled nitric oxide measurement (eNO).

Leicester Cough Questionnaire score correlated closely with cough responsiveness to hypertonic saline and isocapnic hyperpnoea of dry air (Rs -0.66, p<0.001 and Rs -0.49, p=0.002, respectively). Asthma Control Questionnaire also correlated with the cough responsiveness to these challenges (Rs 0.52, p=0.001 and Rs 0.43, p=0.008, respectively). FEV1 (%predicted), diurnal PEF variation and eNO did not correlate with cough-related quality of life but showed some association with asthma control. There was a significant correlation between Leicester Cough Questionnaire and Asthma Control Questionnaire (Rs= -0.54, p=0.001).

Asthma control and cough-related quality of life are more closely associated with cough sensitivity to the investigated cough provocation tests than to eNO and traditional indices of bronchial obstruction. Cough is a major contributor to poor asthma control.
Effect of secreted phospholipase A2 group IID, IIE, and IIF-deficiency on allergen-driven asthma phenotype
Authors: William Henderson, James Bollinger, Jun Xue, Ying-Tzang Tien, Michael Gelb
Journal: European Respiratory Journal (2013)

Rationale : Exaggerated inflammation and remodeling in the airways of patients with asthma occurs through complex Th2 cytokine, chemokine, growth factor, and eicosanoid interactions. The mammalian genome encodes 10 secreted phospholipase A 2  (sPLA 2 )s. The role of these sPLA 2 s in eicosanoid biosynthesis has been unclear. We have found that mice that lack groups X and V (respectively Henderson, W.R., Jr. et al. J Exp Med 2007; 204:865-77 and Henderson, W.R., Jr. et al. PLOS ONE 2013; DOI:10.1371/journal.pone.0056172) sPLA 2 s show reduction in Th2 cytokine-driven airway hyperresponsiveness (AHR) and inflammation. Data are lacking regarding the effect on asthma phenotype of the group IID, IIE, and IIF sPLA 2  enzymes that share a common three-dimensional structure with group V and X sPLA 2 s.   Study Aim : Determine the role of group IID, IIE, and IIF sPLA 2 s in the mediation of airway inflammation and AHR in an ovalbumin (OVA)-induced mouse asthma model.   Results : Airway infiltration by eosinophils (by morphometric analysis) and lung IL-5 release (by qPCR) were decreased in OVA-treated sPLA 2 -IID and IIE knockout (KO) mice compared to wildtype (WT) controls. These parameters of the asthma phenotype were unaffected by sPLA 2 -IIF deficiency. OVA-induced airway mucus metaplasia (by alcian blue histopathology) and AHR (by invasive plethysmography to inhaled methacholine) were not different between WT and sPLA 2 -IID, IIE, and IIF KOs.   Conclusions : These results direct attention to the potential role of group IID and IIE sPLA 2 s in IL-5-mediated trafficking of eosinophils to the airways in allergen-driven asthma.   Research Funding Source : National Institutes of Health grant HL36235.
Disease severity using %predicted and the standardized residual (SR) - A conflict in classification?
Authors: A.H. Kendrick
Journal: European Respiratory Journal (2013)

The SR provides a statistical analysis of normality based on physiological data, whereas the %predicted has little physiological or statistical validity. Commonly used guidelines currently use arbitrary %predicted values as a guide to disease severity. Aim : To assesses the limitations of using %predicted compared to SR. Method : 3474 consecutive datasets (M:1692) aged 20-97yrs (mean 52.9±20.2) for FEV1 were analysed. SR and %predicted values were calculated using the ECCS regression equations, and subdivided based on %predicted. Results : The relationship of %predicted to SR was %pred = 97.6+13.9SR±0.56, r2=0.91.

![Figure][1] 



The relationship did not appear to be influenced by sex or age of the subjects. The distribution of SR values according to %predicted is shown in table 1, and indicates that up to 28% of patients would be misclassified in terms of disease severity.

View this table:

Table 1. Distribution of SR's based on %predicted ranges





Recalculating the approximate %predicted values that equate to the standard SR values on -1.64, -2.5 and -3.5, would give %predicted of 75%, 63% and 49%. Conclusion : The conflict between SR and %predicted remains with current guidelines misclassifying disease severity by %predicted. This may be due to choice of reference equations, which needs to be further investigated.

 [1]: pending:yes