tbuckley/cabot-search huggingface dataset:
Analysis of reactive oxygen species in sputum neutrophils during acute exacerbation of COPD
Authors: Mindaugas Vaitkus, Simona Lavinskiene, Kristina Bieksiene, Jolanta Jeroch, Raimundas Sakalauskas
Journal: European Respiratory Journal (2012)

Background. Chronic airway inflammation in COPD can be mediated by enhanced oxidative burst in neutrophils. Our previous study showed enhanced production of reactive oxygen species (ROS) in peripheral blood neutrophils (PBN) in stable COPD (SCOPD) and during acute exacerbation of COPD (AECOPD).  Aim of the study. To analyze ROS production in sputum neutrophils during AECOPD.  Methods. Thirty-five patients during AECOPD and the same patients in SCOPD, as well as 10 healthy individuals (HI) were involved in to the study. Neutrophils were isolated by high density gradient centrifugation and stimulated with PMA (0.1-30 nM) and S. aureus (1-167 bacteria/neutrophil). ROS production was analysed by flow cytometer.  Results. Spontaneous ROS production in sputum neutrophils was 45.8±3.8% and in PBN 29.7±4.1% higher during AECOPD than in SCOPD (p  Conclusions. ROS production in sputum and peripheral blood neutrophils after stimulation with PMA and S. aureus was more intensive during AECOPD compared with SCOPD. Sputum neutrophils produce higher levels of ROS compare with PBN.
Predictors of mortality in a well-characterised group of patients with COPD
Authors: Saher B. Shaker, Asger Dirksen
Journal: European Respiratory Journal (2012)

Background: COPD is a leading cause of mortality worldwide with an increasing incidence.

Objective: to identify clinical, physiological and radiological predictors of mortality in a well-characterised group of patients with COPD.

Material & methods: patients who participated in 3 clinical trials were included in this study. In these trials, patients were evaluated with clinical data, lung function tests and quantitative computed tomography (relative area of emphysema < -910 HU [RA-910]). The date and cause of mortality were reported during 10 years, and the data of those who were still living by February 1st 2012 were censored at this time point. Data were analysed using Cox proportional hazard regression model first in a univariate model then in a stepwise multiple regression model.

Results: Data from 208 patients with moderate to severe COPD were available. A total of 104 patients died. The median survival time was 10.4 yrs (95% C.I. 9.4-∞). Age, packyears, FEV1, DLCO and RA-910 were significant predictors of mortality in a univariate model. In a multivariate model with a stepwise selection, age (p=0.005), packyears (p=0.02) and RA-910 (p=0.017) emerged as the significant predictors of mortality, whereas FEV1 (p=0.05) and DLCO (p=0.14) did not reach statistical significance.

Conclusion: In this population of smokers with moderate to severe COPD, age, packyears and the degree of emphysema on CT as RA-910 were the most important predictors of mortality.
Preclinical Efficacy of the MDM2 Inhibitor RG7112 in <i>MDM2</i>-Amplified and <i>TP53</i> Wild-type Glioblastomas
Authors: Maite Verreault, Charlotte Schmitt, Lauriane Goldwirt, Kristine Pelton, Samer Haidar, Camille Levasseur, Jeremy Guehennec, David Knoff, Marianne Labussière, Yannick Marie, Azra H. Ligon, Karima Mokhtari, Khê Hoang-Xuan, Marc Sanson, Brian M. Alexander, Patrick Y. Wen, Jean-Yves Delattre, Keith L. Ligon, Ahmed Idbaih
Journal: Clinical Cancer Research (2015)

Abstract Purpose: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Experimental Design: We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. Results: MDM2-amplified PDCLs were 44 times more sensitive than TP53-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μmol/L vs. 21.9 μmol/L). MDM4-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μmol/L), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μmol/L). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood–brain and the blood–tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusions: These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non–MDM2-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified. Clin Cancer Res; 22(5); 1185–96. ©2015 AACR.
Abstract 15418: Mir590 Variant rs6971711 Identified in African-American HCM Patients Reduces Mature MiR590 Biogenesis and Target Gene Expression
Authors: Xiaoping Lin, Steven Steinberg, Scot J Matkovich, Sarah Wheelan, Junaid Afzal, Blaid Mbiyangandu, Neal Epstein, Dotti Tripodi, Zhaoxia Huo, Gary Cutting, Theodore P Abraham, Roselle Abraham
Journal: Circulation (2014)

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiovascular disorders characterized by myocyte hypertrophy/disarray and fibrosis. Genotype-phenotype correlations indicate phenotypic heterogeneity and variable penetrance, indicating influence of modifier genes. Recent studies reveal that variants in microRNAs (miRs) can lead to disease.   Aim:  The goal was to identify genetic variations in miRs that could have functional effects, in HCM patients.   Methods:  Direct sequencing of 18 miRs (selected by literature mining) was performed in 199 HCM patients. The 1000 Genomes Project database was used to obtain matched population allele and genotype frequency. Real-time qPCR and luciferase assay were performed in HEK293T cells to assess functional effects of the miR variant.   Results:  Eleven variants in 9/18 miRs were identified in 89 HCM patients. Our novel result is a SNP rs6971711 (72C>T) , located in  mature  miR-590-3 p , a regulator of post-natal cardiac myocyte proliferation. This SNP was present in 5 patients, all African-Americans. SNP frequency in HCM patients (0.227) was markedly higher than its frequency in the 1000 Genomes Project database. Alignment of pre-miR sequences revealed that  rs6971711  is located in a highly conserved region in mammals.  Mutant miR-590 (hsa-pri-miR-590; 72T) transfection in HEK293T cells resulted in 9 fold reduction of mature miR-590-5 p  levels and 49 fold decrease of miR-590-3 p  levels when compared to wild type (hsa-pri-miR-590; 72C), indicating  reduced miR-590 biogenesis . The 3’ UTR of TGF-β receptor type II (TGFBR2) was chosen to examine the functional change caused by 72C>T in miR-590 because it is an experimentally-validated miR-590-5 p  target and important in TGF-β signaling/fibrosis. Over-expression of wild type miR-590 suppressed luciferase activity ~5fold, while the mutant significantly reduced (p p  [[Unable to Display Character: –]] hence the SNP could predispose to cardiac fibrosis.   Conclusion:  This is the first report of a miR SNP ( rs6971711)  with high frequency in African-American HCM patients and  loss of function effect on miR-590-3 p /5 p biogenesis and target gene (TGFBR2) suppression, which could influence left ventricular mass and fibrosis.
Prevalence of Electrocardiographic Anomalies in Young Individuals
Authors: Navin Chandra, Rachel Bastiaenen, Michael Papadakis, Vasileios F. Panoulas, Saqib Ghani, Jennifer Duschl, David Foldes, Hariharan Raju, Rebecca Osborne, Sanjay Sharma
Journal: Journal of the American College of Cardiology (2014)
Reflections on reflections
Authors: B. Lovell
Journal: BMJ (2015)

I am very angry. Today I had a professional disagreement with a surgical colleague. He came to review a patient and somehow managed to criticise the nurses, offend our occupational therapist, denigrate the quality of the referral, and say something to a foundation doctor, who disappeared to the toilet for 15 minutes and emerged distinctly red eyed and blotchy faced. After the colleague left I managed to achieve “blistering rage” in about 90 seconds. I was so eye wateringly furious I could barely form coherent sentences. …
Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes
Authors: András N. Spaan, Tamara Reyes-Robles, Cédric Badiou, Sylvie Cochet, Kristina M. Boguslawski, Pauline Yoong, Christopher J. Day, Carla J.C. de Haas, Kok P.M. van Kessel, François Vandenesch, Michael P. Jennings, Caroline Le Van Kim, Yves Colin, Jos A.G. van Strijp, Thomas Henry, Victor J. Torres
Journal: Cell Host & Microbe (2015)
Abstract 1492: Prediction of cancer progression in Barrett's esophagus patients using miRNA profiling
Authors: Josef Srovnal, Ondrej Slaby, Jiri Ehrmann, Jan Gregar, Lenka Radova, Michaela Sedlackova, Marian Hajduch
Journal: Cancer Research (2014)

Abstract Background: Barrett's esophagus (BE) is a metaplastic disease with risk to develop esophageal adenocarcinoma (EAC). Current screening method for BE patients (endoscopy and biopsy) is discomfort, expensive and relatively risky for patients. Moreover, the procedure is complicated by subjective histopathological examination. Approximately only 2% of BE patients annually progress to adenocarcinoma. The aim of our study was to identify miRNA profiles in order to predict cancer progression in high-risk BE patients. Methods and patients: FFPE samples were obtained from 68 patients (10 EAC, 4 high-grade and 21 low-grade dysplasia of esophagus, and 33 BE). There were 49 males and 19 females; median age was 58 years, range 27 - 97 years. Total RNA was purified from FFPE biopsy samples using Proteinase K treatment followed by RNeasy kit (Qiagen). Microarray analysis was performed using the GeneChip miRNA 3.0 Array (Affymetrix). The data were analyzed using “R” software and the Bioconductor package. Results: In total, 68 GeneChip miRNA 3.0 Arrays were performed in 68 patients (8 poor quality arrays were excluded). Expression profiles of 1733 human miRNAs, 1658 human pre-miRNAs and 2216 human sno-RNAs and sca-RNAs were analyzed. In supervised clustering analysis we found 29 differentially expressed miRNAs, 7 pre-miRNAs and 9 sno-RNAs (p&amp;lt;0.001 or logFC &amp;lt;-2 or logFC &amp;gt;2) in EAC patients compared to BE patients. One of the dominant findings was decreased expression of miR-22 in EAC samples, which is known to function as a tumor suppressor and histone deacetylase 4 regulator. Conclusion: We have identified miRNA profiles allowing for better diagnostics of cancer progression in BE patients, which, however, will require further validation. Acknowledgment: This work was financially supported by IGA MZ CR NT13585-3/202, IGA UP LF 2013_015, CZ.1.05/2.1.00/01.0030 and CZ.1.07/2.3.00/30.0004. Citation Format: Josef Srovnal, Ondrej Slaby, Jiri Ehrmann, Jan Gregar, Lenka Radova, Michaela Sedlackova, Marian Hajduch. Prediction of cancer progression in Barrett's esophagus patients using miRNA profiling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1492. doi:10.1158/1538-7445.AM2014-1492
Second acute leukemia and other malignancies following treatment for Hodgkin's disease.
Authors: P Valagussa, A Santoro, F Fossati-Bellani, A Banfi, G Bonadonna
Journal: Journal of Clinical Oncology (1986)

The records of 1,329 patients with Hodgkin's disease admitted from 1965 to 1982 were analyzed to assess the relative frequency of second neoplasms. Within a median follow-up of 9.5 years, a total of 68 new cancers were documented. Nineteen cases of acute nonlymphocytic leukemia, 6 cases of non-Hodgkin's lymphomas, and 43 cases with different types of solid tumors were identified. The overall risk of non-Hodgkin's lymphoma was 1.3% +/- 0.6% and of solid tumors was 8.3% +/- 1.5% when basal cell carcinomas were included and 6.7% +/- 1.4% when basal cell carcinomas were excluded. No cases of leukemia were documented in patients treated with radiation therapy only. The 12-year estimate of leukemia by treatment was as follows: chemotherapy only 1.4% +/- 2.3%; radiation plus MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) 10.2% +/- 5.2%; radiation plus ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) 0; and radiation plus other drug regimens 4.8% +/- 1.6%. The risk of leukemia was particularly high (15.5% +/- 7.4%) in patients who received salvage MOPP after radiation failure. A positive association was also noted between increasing age and risk of second malignancies, especially leukemia. The incidence of second neoplasms can be markedly decreased by deleting from potentially curative therapy certain drugs such as alkylating agents, procarbazine, and nitrosourea derivatives.
Aging and Cancerigenesis. IV. Interrelationships Among Age, Immune Response, and Tumor Incidence in Several Strains of Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Morris N. Teller, Marion Eilbert
Journal: JNCI Journal of the National Cancer Institute (1967)

Immune reactivity of mice with various incidences of spontaneous tumors was measured at different points in their lifespan. Cytotoxic activity of immune sera from 3- and 12-month-old mice was high or moderately high in AKR/J, SJL/J, and A/HeJ mice in which high incidences of spontaneous tumors occur by the 12th month, and in SWR/J and C3HeB/-FeJ mice in which high incidences of spontaneous tumors reportedly occur after 18 months of age. A decrease in primary antibody response accompanied old age in 4 of the 6 strains tested (including randombred Swiss ICR/Ha), but not in AKR/J or A/HeJ mice. These facts, together with previous tests of cellular response in these mice, imply that under these experimental conditions little correspondence exists between humoral and cellular response. Further, host immunity may be only secondarily implicated in neoplastic formation.
Detection of non-tuberculosis mycobacteria (NTM) in bronchoscopy specimens using molecular techniques
Authors: Dushantha Madegedara, Dulanthi K. Weerasekera, Dammika Magana Arachchi
Journal: European Respiratory Journal (2013)

Background NTM include mycobacteria not belonging to the Mycobacterium tuberculosis complex. This study was performed to optimize a simple assay based on Polymerase Chain Reaction (PCR) and restriction enzyme digestion for diagnosis of mycobacterial infection.  Methods Bronchoscopy specimens (n=202) were collected from patients attending the Teaching Hospital Kandy. DNA extracted from the AFB positive colonies (n=46) were amplified using known mycobacterial specific Sp1 and Sp2 primers. DNA sequencing was performed and the sequenced strains were digested withHae III and Cfo I.  Results Four isolates were rapid growers (∼280-320 bp), 21 were slow growers (∼200-220 bp) and 15 cultures had both rapid and slow growing mycobacteria. Sequence analysis revealed the presence of Nocardia, M. intracellulare and M. phocaicum. M. tuberculosis and Mycobacterium sp. Hae III digestion of H37Rv and M. bovis yielded 50 bp and 110 bp DNA fragments while M. phocaicum had 120 bp and 200 bp bands, Nocardiayielded 150 bp and 160 bp DNA fragments and M. intracellulare a 100 bp DNA fragment. Cfo I cleavage sites were not present in H37Rv, M. bovis, Nocardia and M. intracellulare hence remained undigested while M. phocaicum yielded 80 bp and 230 bp DNA fragments. Hae III along with only Cfo I was inadequate to differentiate M. tuberculosis complex isolates from M. intracellulare. PCR was able to differentiate the slow and rapid growers.  Conclusion Molecular analysis confirmed the presence of NTM in bronchoscopy specimens and 11% of the study population was suffering from NTM diseases. The involvement of acid–fast NTM in tuberculosis like syndromes might result in the misdiagnosis of tuberculosis.
A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.
Authors: C J Logothetis, F H Dexeus, L Finn, A Sella, R J Amato, A G Ayala, R G Kilbourn
Journal: Journal of Clinical Oncology (1990)

To evaluate the relative efficacy of cisplatin, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (CISCA) versus methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), a prospective randomized trial was performed in patients with advanced metastatic urothelial tumors. Patients were stratified by histologic disease type and degree of tumor dissemination. Equal distribution of the clinical characteristics was achieved. One hundred ten patients with metastatic disease of the urinary tract (86 bladder, 16 renal pelvis, seven ureter, one prostatic urethra) met eligibility criteria and were enrolled on study. These represented 82% of the total patients seen during the study period in the Section of Genitourinary Oncology who met the eligibility criteria. The combined complete and partial response rate was significantly higher for patients treated with MVAC than for those treated with CISCA (65% v 46%; P less than .05). The survival duration of MVAC-treated patients was significantly longer than that of CISCA-treated patients (mean, 62.6 weeks; median, 48.3; range, 5.0+ to 162.3+ v mean, 40.4 weeks; median, 36.1; range, 7+ to 147.1+). We conclude that MVAC chemotherapy is superior to CISCA chemotherapy, achieving a higher response rate and a longer survival for equivalent patients with metastatic urothelial tumors.
Completely scoobied: the confusing world of temperature and pollution effects on sleep apnoea
Authors: Nathaniel S. Marshall, Christine T. Cowie
Journal: European Respiratory Journal (2015)

Aficionados of 1970s and 1980s cartoons will have no trouble imagining the look of befuddlement upon our faces reminiscent of Scooby Doo's when presented with a new mystery. Normally in an editorial, one should write a nice, succinct summary of the field providing the reader with a clear but concise understanding of where we are and where we are heading. However, it is just not possible in this case. The evidence is truly befuddling. The four key studies [1–4] are not just inconsistent with respect to the effects of temperature on sleep apnoea, they are clearly contradictory and it is not clear why. So, this will be an editorial that poses more questions than it answers. Four key studies clearly contradictory over the effects of temperature on sleep apnoea and it is not clear why <http://ow.ly/RWg41>
Human neutrophil peptides as biotracers of functional impairment in COPD smokers
Authors: Gregorino Paone, Giovanni Schmid, Vittoria Conti, Fulvio Benassi, Gilda Giannunzio, Giovanni Puglisi
Journal: European Respiratory Journal (2012)

Background  Human Neutrophil Peptides (HNP) are small molecular weight peptides abundant in neutrophils, which may be released upon activation in the extracellular environment. Nearly absent in the normal lung, HNP have been found increased in airways of patients with neutrophil related inflammatory lung diseases. Recently the presence of HNP has been demonstrated in the lung of current smokers.   Aim  We aimed to assess whether sputum HNP concentrations could be used to trace pulmonary functional impairment during COPD clinical course.   Methods  A consecutive population of 138 smokers with and without COPD was referred to our smoking cessation centre. All participants underwent physical examination, pulmonary function tests; sputum samples were collected at enrolment.   Results  We evaluated 42 symptomatic smokers; 8 individuals with COPD stage 1; 18 subjects with COPD stage 2; 19 individuals with stage 3 disease and 51 patients with COPD stage 4 .  The HNP sputum concentrations were significantly higher in participants with COPD as compared to symptomatic smokers without airway obstruction (26.6 ± 11.5 μg/ml vs 1.9 ± 0.8 μg/ml;  p  p   Importantly HNP sputum levels showed a highly significant negative correlation with FEV1 and with FEV1/FVC (r= -0.75, p   Conclusion  Our findings suggest that HNP, a major product released by activated neutrophils, may have a role in monitoring lung inflammation and may be used to trace airway obstruction during COPD clinical course.
Vardenafil in Pulmonary Arterial Hypertension
Authors: Zhi-Cheng Jing, Zai-Xin Yu, Jie-Yan Shen, Bing-Xiang Wu, Kai-Feng Xu, Xian-Yang Zhu, Lei Pan, Zhuo-Li Zhang, Xue-Qin Liu, Yu-Shun Zhang, Xin Jiang, Nazzareno Galiè
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events.To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH.In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks.At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events.Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.
Cellular composition of bronchial brush-biopsies at COPD exacerbation
Authors: Sophia Nesterovich, Ekaterina Bukreeva
Journal: European Respiratory Journal (2012)

46 COPD exacerbation patients were examined. Cytological research of brush-biopsies were taken at bronchoscopy was made; for verification of infectional nature of COPD exacerbation the quantitative bacteriological sputum research, definition of diagnostic main IgG, IgM levels to Ch.pneumoniae, M.pneumoniae in serum by means immuno-assay method, definition of their genomes fragments in sputum by means of PCR method were made. Kruskal – Wallis criterion was used.  Infectional character of COPD exacerbation was confirmed at 36 patients. Typical cells count in H.influenzae, Ch.pneumoniae, M.pneumoniae infection was 14.6±2.2%, 15.1±2.5%, 15.5±3.1%, that was reliable low (p  Infectional agent species influence on degree of bronchial mucosa damage. H.influenzae, Ch.pneumoniae have more injured effects and M.catarrhalis have least injured effects.