bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNAi screening of the kinome with cytarabine in leukemias
Authors: Tibes Raoul , Bogenberger James M. , Chaudhuri Leena , Hagelstrom R. Tanner , Chow Donald , Buechel Megan E. , Gonzales Irma M. , Demuth Tim , Slack James , Mesa Ruben A. , Braggio Esteban , Yin Hongwei H. , Arora Shilpi , Azorsa David O. 
Published: January 2012

AbstractTo identify rational therapeutic combinations with cytarabine (Ara-C), we developed a high-throughput, small-interference RNA (siRNA) platform for myeloid leukemia cells. Of 572 kinases individually silenced in combination with Ara-C, silencing of 10 (1.7%) and 8 (1.4%) kinases strongly increased Ara-C activity in TF-1 and THP-1 cells, respectively. The strongest molecular concepts emerged around kinases involved in cell-cycle checkpoints and DNA-damage repair. In confirmatory siRNA assays, inhibition of WEE1 resulted in more potent and universal sensitization across myeloid cell lines than siRNA inhibition of PKMYT1, CHEK1, or ATR. Treatment of 8 acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) cell lines with commercial and the first-in-class clinical WEE1 kinase inhibitor MK1775 confirmed sensitization to Ara-C up to 97-fold. Ex vivo, adding MK1775 substantially reduced viability in 13 of 14 AML, CML, and myelodysplastic syndrome patient samples compared with Ara-C alone. Maximum sensitization occurred at lower to moderate concentrations of both drugs. Induction of apoptosis was increased using a combination of Ara-C and MK1775 compared with using either drug alone. WEE1 is expressed in primary AML, ALL, and CML specimens. Data from this first siRNA-kinome sensitizer screen suggests that inhibiting WEE1 in combination with Ara-C is a rational combination for the treatment of myeloid and lymphoid leukemias.
Trastuzumab for treatment of refractory/relapsed HER2-positive adult B-ALL: results of a phase 2 GRAALL study
Authors: Chevallier Patrice , Robillard Nelly , Charbonnier Aude , Raffoux Emmanuel , Maury Sebastien , Carras Sylvain , Chabrot Cecile , Fohrer Cecile , Bernard Marc , Blade Jean-Sebastien , Etienne Anne , Talmant Pascaline , Delaunay Jacques , Guillaume Thierry , Mohty Mohamad , Bene Marie-Christine , Ifrah Norbert , Dombret Herve 
Published: January 2012

Abstract
The aim of this phase 2 study was to evaluate the efficacy and safety of trastuzumab, a humanized monoclonal antibody targeted against the human epidermal growth factor receptor 2 (HER2), for adult patients with relapsed/refractory HER2-positive B-ALL. Fifteen patients, with a median age of 62 years, received trastuzumab according to the schedule approved for breast cancer patients (ie, 4 mg/kg intravenous loading dose followed by 2 mg/kg weekly). The overall response rate was 13% with 2 patients achieving partial response and partial remission cytolytic response, respectively. Two other patients were documented with blast clearance. Only 1 reversible grade 3 cardiac toxic event occurred. This phase 2 study showed that trastuzumab monotherapy can allow for some responses in a very high-risk refractory/relapsed HER2-positive adult B-ALL population. Combination of trastuzumab with chemotherapy or other therapeutic monoclonal antibodies should be tested in the future. This trial was registered at www.clinicaltrials.gov/ct as NCT00724360.
Proteins involved in extracellular matrix dynamics are associated with respiratory syncytial virus disease severity
Authors: Schuurhof Annemieke , Bont Louis , Hodemaekers Hennie M. , de Klerk Arja , de Groot Hanneke , Hofland Regina W. , van de Pol Alma C. , Kimpen Jan L.L. , Janssen Riny 
Published: January 2012

Severity of respiratory syncytial virus (RSV) infection ranges widely. To what extent the local immune response is involved in RSV disease pathogenesis and which markers of this response are critical in determining disease severity is still a matter of debate.The local immune response was studied in nasopharyngeal aspirates (NPAs) during RSV infection. 47 potential markers of disease severity were analysed in a screening cohort of RSV-infected infants with mild disease at home (n=8), hospitalised infants (n=10) and infants requiring mechanical ventilation (n=7). Results were confirmed in a cohort of infants hospitalised for RSV infection (n=200). Finally, genetic validation was studied in a cohort of infants hospitalised for RSV infection (n=465) and healthy controls (n=930).The concentration of TIMP-1 (tissue inhibitor of metalloproteinase) was higher in the NPAs of hospitalised infants compared with the NPAs of infants at home (1,199versus568 ng·mL−1; p<0.0001). Similar results were found for matrix metalloproteinase (MMP)-3 (765versus370 pg·mL−1; p=0.004). MMP-3 was confirmed as a marker of disease severity in a larger cohort andMMP3gene polymorphism rs522616 was associated with severe RSV infection (OR 0.82, p<0.05).In conclusion, extracellular matrix proteinases play an important role in the pathogenesis of RSV bronchiolitis.
DNA damage as a molecular link in the pathogenesis of COPD in smokers
Authors: Aoshiba Kazutetsu , Zhou Fang , Tsuji Takao , Nagai Atsushi 
Published: January 2012

In this study, we investigated whether DNA double-strand breaks (DSBs) contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD).We immunofluorescence-stained lung tissue samples obtained from COPD patients, asymptomatic smokers and nonsmokers for markers of DSBs.The numbers of DSB foci (phosphorylated histone 2AX (γH2AX), phosphorylated ATM (ataxia telangiectasia mutated) substrate and phosphorylated p53-binding protein-1 foci) per cell in alveolar type I and II cells and endothelial cells were higher in the COPD patients than in the asymptomatic smokers and nonsmokers. The lung tissue in which type II cells contained higher numbers of γH2AX foci per cell had higher percentages of type II cells that expressed p16INK4a(p16), phosphorylated nuclear factor (NF)-κB and interleukin (IL)-6, and of alveolar wall cells that expressed active caspase-3. The type II cells that contained higher numbers of γH2AX foci per cell had higher rates of expression of p16, phosphorylated NF-κB, and IL-6. Half of the alveolar wall cells that expressed active-caspase-3 contained γH2AX foci. Type II cells that stained positive for 8-hydroxy-2-deoxyguanosine contained a higher number of γH2AX foci per cell than the type II cells that stained negative.In conclusion, DSBs, at least in part caused by oxidative stress, appear to contribute to the pathogenesis of COPD by inducing apoptosis, cell senescence and pro-inflammatory responses.
Mechanical properties of asthmatic airway smooth muscle
Authors: Chin Leslie Y.M. , Bossé Ynuk , Pascoe Chris , Hackett Tillie L. , Seow Chun Y. , Paré Peter D. 
Published: January 2012

Airway smooth muscle (ASM) is the major effector of excessive airway narrowing in asthma. Changes in some of the mechanical properties of ASM could contribute to excessive narrowing and have not been systematically studied in human ASM from nonasthmatic and asthmatic subjects.Human ASM strips (eight asthmatic and six nonasthmatic) were studied atin situlength and force was normalised to maximal force induced by electric field stimulation (EFS). Measurements included: passive and active forceversuslength before and after length adaptation, the force–velocity relationship, maximal shortening and force recovery after length oscillation. Force was converted to stress by dividing by cross-sectional area of muscle.The only functional differences were that the asthmatic tissue was stiffer at longer lengths (p<0.05) and oscillatory strain reduced isometric force in response to EFS by 19% as opposed to 36% in nonasthmatics (p<0.01).The mechanical properties of human ASM from asthmatic and nonasthmatic subjects are comparable except for increased passive stiffness and attenuated decline in force generation after an oscillatory perturbation. These data may relate to reduced bronchodilation induced by a deep inspiration in asthmatic subjects.
Prognostic value ofTP53,KRASandEGFRmutations in nonsmall cell lung cancer: the EUELC cohort
Authors: Scoccianti Chiara , Vesin Aurélien , Martel Ghislaine , Olivier Magali , Brambilla Elisabeth , Timsit Jean-François , Tavecchio Luca , Brambilla Christian , Field John K. , Hainaut Pierre ,   the European Early Lung Cancer Consortium
Published: January 2012

Nonsmall cell lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in theTP53,KRASandEGFRgenes.The series included 11 never-smokers, 86 former smokers, 152 current smokers and one patient without informed smoking status. There were 110 squamous cell carcinomas (SCCs), 133 adenocarcinomas (ADCs) and seven large cell carcinomas or mixed histologies. Expression of p53 was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues.TP53mutations were detected in 48.8% of cases and were more frequent among SCCs than ADCs (p<0.0001).TP53mutation status was not associated with prognosis. G to T transversions, known to be associated with smoking, were marginally more common among patients who developed a second primary lung cancer or recurrence/metastasis (progressive disease).EGFRmutations were almost exclusively found in never-smoking females (p=0.0067).KRASmutations were detected in 18.5% of cases, mainly ADC (p<0.0001), and showed a tendency toward association with progressive disease status.These results suggest that mutations are good markers of different aetiologies and histopathological forms of lung cancers but have little prognostic value, with the exception ofKRASmutation, which may have a prognostic value in ADC.
The European Respiratory Society spirometry tent: a unique form of screening for airway obstruction
Authors: Maio Sara , Sherrill Duane L. , MacNee William , Lange Peter , Costabel Ulrich , Dahlén Sven-Erik , Sybrecht Gerhard W. , Burghuber Otto C. , Stevenson Robin , Tønnesen Philip , Haeussinger Karl , Hedlin Gunilla , Bauer Torsten T. , Riedler Josef , Nicod Laurent , Carlsen Kai-Håkon , Viegi Giovanni 
Published: January 2012

In order to raise public awareness of the importance of early detection of airway obstruction and to enable many people who had not been tested previously to have their lung function measured, the European Lung Foundation and the European Respiratory Society (ERS) organised a spirometry testing tent during the annual ERS Congresses in 2004–2009.Spirometry was performed during the ERS Congresses in volunteers; all participants answered a simple, brief questionnaire on their descriptive characteristics, smoking and asthma. Portable spirometers were freely provided by the manufacturer. Nurses and doctors from pulmonary departments of local hospitals/universities gave their service for free. Lower limit of normal (LLN) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for diagnosing and grading airway obstruction were used.Of 12,448 participants in six congress cities, 10,395 (83.5%) performed acceptable spirometry (mean age 51.0±18.4 yrs; 25.5% smokers; 5.5% asthmatic). Airway obstruction was present in 12.4% of investigated subjects according to LLN criteria and 20.3% according to GOLD criteria. Through multinomial logistic regression analysis, age, smoking habits and asthma were significant risk factors for airway obstruction. Relative risk ratio and 95% confidence interval for LLN stage I, for example, was 2.9 (2.0–4.1) for the youngest age (≤19 yrs), 1.9 (1.2–3.0) for the oldest age (≥80 yrs), 2.4 (2.0–2.9) for current smokers and 2.8 (2.2–3.6) for reported asthma diagnosis.In addition to being a useful advocacy tool, the spirometry tent represents an unusual occasion for early detection of airway obstruction in large numbers of city residents with an important public health perspective.
A novel subpopulation of monocyte-like cells in the human lung after lipopolysaccharide inhalation
Authors: Brittan Mairi , Barr Laura , Conway Morris Andrew , Duffin Rodger , Rossi Fiona , Johnston Shonna , Monro Graham , Anderson Niall , Rossi Adriano G. , McAuley Danny F. , Haslett Christopher , Hirani Nik , Dhaliwal Kev , Simpson A. John 
Published: January 2012

The co-ordinated recruitment of monocyte subpopulations, neutrophils and regulatory T-cells (Tregs) during the early stages of human acute lung inflammation remains poorly understood. We therefore performed a detailed characterisation of these lineages in the blood and lungs in a model of human acute lung inflammation.Healthy volunteers inhaled lipopolysaccharide (LPS) or saline (n=6 for each group). Blood was collected at 0, 2, 4, 6 and 8 h and bronchoscopy with bronchoalveolar lavage (BAL) performed at 8 h. Multiparameter flow cytometry was used to characterise monocyte subpopulations, neutrophils and Tregs in the blood and lung.Inhalation of LPS was associated with significant blood and BAL fluid neutrophilia. Blood populations of monocyte subpopulations and Tregs were unaltered by LPS. In contrast, LPS induced an accumulation of a pulmonary monocyte-like cell (PMLC) population, which was further subdivided into “inducible” CD14++CD16-and “resident” CD14++CD16+subsets. Inducible PMLCs were significantly increased following LPS inhalation (p=0.0046), whereas resident PMLCs were unchanged. In addition, we noted a significant decrease in Tregs in BAL fluid with LPS inhalation (p=0.027).The early stages of LPS-induced inflammation in humans is characterised by pulmonary accumulation of a novel inducible monocyte-like subpopulation, accompanied by significant changes in both neutrophil and Treg numbers.
Two novel, severe asthma phenotypes identified during childhood using a clustering approach
Authors: Just Jocelyne , Gouvis-Echraghi Rahele , Rouve Sarah , Wanin Stephanie , Moreau David , Annesi-Maesano Isabella 
Published: January 2012

Unsupervised cluster analysis has already been used to identify severe phenotypes of childhood asthma, but without taking into account inflammatory markers. The aim of this study was to define independent homogeneous phenotypic clusters of severe asthma in a cohort of asthmatic children.Cluster analysis was applied to 19 variables from 315 children enrolled in the Trousseau Asthma Program in Paris, France.Three independent clusters of asthma were identified. Cluster 1, asthma with severe exacerbations and multiple allergies: 103 children had more sensitisations to inhaled allergens and food allergens, more blood eosinophils and basophils, more uncontrolled asthma despite high doses of inhaled corticosteroid and more hospitalisations for exacerbation. Cluster 2, severe asthma with bronchial obstruction: 72 children were significantly older, had the highest body mass index, a lower forced expiratory volume in 1 s, more pronounced blood neutrophils and significantly higher levels of all classes of immunoglobulin (Ig), except IgE. Cluster 3, mild asthma: 140 children did not show statistically significant features.These results could lead to improved management of severe asthma in children by optimising treatment strategies,i.e.anti-allergic drugs, such as anti-IgE for children with the allergic phenotype, and anti-neutrophil drugs, such as macrolides for those with the obstructive phenotype.
Breath analysis during one-lung ventilation in cancer patients
Authors: Kischkel Sabine , Miekisch Wolfram , Fuchs Patricia , Schubert Jochen K. 
Published: January 2012

Noninvasive breath analysis may provide valuable information for cancer recognition if disease-specific volatile biomarkers could be identified. In order to compare nondiseased and diseased tissuein vivo, this study took advantage of the special circumstances of one-lung ventilation (OLV) during lung-surgery.15 cancer patients undergoing lung resection with OLV were enrolled. From each patient, alveolar breath samples were taken separately from healthy and diseased lungs before and after tumour resection. Volatile substances were pre-concentrated by means of solid-phase microextraction, and were separated, identified and quantified by means of gas chromatography–mass spectrometry.Different classes of volatile substances could be identified according to their concentration profiles. Due to prolonged fasting and activation of lipolysis, concentrations of endogenous acetone significantly increased during surgery. Exogenous substances, such as benzene or cyclohexanone, showed typical washout exhalation kinetics. Exhaled concentrations of potentially tumour associated substances, such as butane or pentane, were different for nondiseased and diseased lungs and decreased significantly after surgery.Separate analysis of volatile substances exhaled from healthy and diseased lungs in the same patient, together with thorough consideration of substance origins and exhalation kinetics offers unique opportunities of biomarker recognition and evaluation.
Costs of childhood asthma due to traffic-related pollution in two California communities
Authors: Brandt Sylvia J. , Perez Laura , Künzli Nino , Lurmann Fred , McConnell Rob 
Published: January 2012

Recent research suggests the burden of childhood asthma that is attributable to air pollution has been underestimated in traditional risk assessments, and there are no estimates of these associated costs. We aimed to estimate the yearly childhood asthma-related costs attributable to air pollution for Riverside and Long Beach, CA, USA, including: 1) the indirect and direct costs of healthcare utilisation due to asthma exacerbations linked with traffic-related pollution (TRP); and 2) the costs of health care for asthma cases attributable to local TRP exposure.We calculated costs using estimates from peer-reviewed literature and the authors’ analysis of surveys (Medical Expenditure Panel Survey, California Health Interview Survey, National Household Travel Survey, and Health Care Utilization Project). A lower-bound estimate of the asthma burden attributable to air pollution was US$18 million yearly. Asthma cases attributable to TRP exposure accounted for almost half of this cost. The cost of bronchitic episodes was a major proportion of both the annual cost of asthma cases attributable to TRP and of pollution-linked exacerbations.Traditional risk assessment methods underestimate both the burden of disease and cost of asthma associated with air pollution, and these costs are borne disproportionately by communities with higher than average TRP.
Measurement of parasternal intercostal electromyogram during an infective exacerbation in patients with cystic fibrosis
Authors: Reilly Charles C. , Jolley Caroline J. , Elston Caroline , Moxham John , Rafferty Gerrard F. 
Published: January 2012

The parasternal intercostal muscle electromyogram (sEMGpara) is a measure of neural respiratory drive and reflects lung disease severity in stable cystic fibrosis (CF). The aim of the study was to measure sEMGpara in acute infective exacerbations of CF and compare changes in sEMGpara with those in conventional lung function measures.12 patients with CF admitted to hospital with an acute chest infection were studied.There was a significant reduction in mean±sdsEMGpara (ΔsEMGpara -38±19%, p<0.001) between admission and discharge. Spirometery also improved significantly from admission to discharge; Δforced expiratory volume in 1 s % predicted 39±30%, p<0.001 and Δvital capacity % pred 22±18%, p<0.001.sEMGpara has potential value as a nonvolitional measure of change in respiratory function in CF.
GenoType MTBDRslperformance on clinical samples with diverse genetic background
Authors: Miotto Paolo , Cabibbe Andrea M. , Mantegani Paola , Borroni Emanuele , Fattorini Lanfranco , Tortoli Enrico , Migliori Giovanni B. , Cirillo Daniela M. 
Published: January 2012

We evaluate the performance of the GenoType® MTBDRsl(Hain Lifescience Nehren, Germany) for the detection of second-line resistant tuberculosis and we correlate the frequency of mutations to differentMycobacterium tuberculosisgenotypes.We tested 175 strains and 59 clinical specimens interpreting the results according to the Standards for Reporting of Diagnostic Accuracy recommendations. All the strains were also investigated by spoligotyping and Mycobacterial Interspersed Repetitive Units–Variable Number of Tandem Repeats typing.The performances of the MTBDRslin detecting resistance to fluoroquinolones (FQ), second-line injectable drugs (SLID), and ethambutol (EMB) on clinical isolates were similar (specificity ∼99%, sensitivity ∼70%, and positive predictive value (PPV) ∼99%).Of the 59 respiratory specimens, three samples were classified as “indeterminate”. The specificity in detecting resistances was similar for FQs and EMB 100% (95% CI 92.7–100%) and 100% (95% CI 83.9–100%), respectively with a PPV of 100% (95% CI 64.6–100%) and 100% (95% CI 87.9–100%), respectively. Detection of SLID showed a specificity of 89.1% (95% CI 77.0–95.3%) and a PPV of 58.3% (95% CI 32.0–80.7%). Sensitivity for FQ-resistance detection was 100% (95% CI 64.6–100%), whereas for SLID and EMB it was 89.1% (95% CI 77.0-95.3%) and 86.1% (95% CI 71.3-93.9%), respectively. We detected a significant association between mutations in therrsgene and Beijing lineage.The MTBDRslcan be used to “rule in” extensively drug-resistant strains of tuberculosis in a high risk group; the low sensitivity and negative predicted value (NPV) make confirmation by conventional drug susceptibility testing mandatory when mutations are not identified. NPV for SLID is higher in Beijing strains, showing that the predictive values of the molecular tests are related to the genetic background.
Community-acquired pneumonia in outpatients: aetiology and outcomes
Authors: Cillóniz Catia , Ewig Santiago , Polverino Eva , Marcos Maria Angeles , Prina Elena , Sellares Jacobo , Ferrer Miquel , Ortega Mar , Gabarrús Albert , Mensa Josep , Torres Antoni 
Published: January 2012

The purpose of this study was to establish the microbial aetiology and outcomes of patients with community-acquired pneumonia (CAP) treated as outpatients after presenting to a hospital emergency care unit.A prospective observational study was carried out in the Hospital Clinic of Barcelona (Barcelona, Spain). All consecutive cases of CAP treated as outpatients were included.568 adult outpatients with CAP were studied (mean±sdage 47.2±17.6 yrs; 110 (19.4%) were aged ≥65 yrs). Aetiological diagnoses were established in 188 (33.1%) cases.Streptococcus pneumoniaewas the most frequent pathogen followed byMycoplasma pneumoniaeand respiratory viruses.Legionellawas detected in 13 (2.3%) cases. More than one causative agent was found in 17 (9.0%) patients. Mortality was low (three (0.5%) patients died) and other adverse events were rare (30 (5.2%) patients had complications, 13 (2.3%) were re-admitted and treatment failed in 13 (2.3%)). Complications were mostly related to pleural effusion and empyema, and re-admissions and treatment failures to comorbidities.Outpatients with CAP have a characteristic microbial pattern. Regular antipneumococcal coverage remains mandatory. Treatment failures and re-admissions are rare and may be reduced by increased attention to patients requiring short-term observation in the emergency care unit and in the presence of pleural effusion and comorbidities.