tbuckley/cabot-search huggingface dataset:
Detection of exacerbations in asthma based on electronic diary data: results from the 1-year prospective BIOAIR study
Authors: Maciej Kupczyk, Shushila Haque, Peter J Sterk, Ewa Niżankowska-Mogilnicka, Alberto Papi, Elisabeth H Bel, Pascal Chanez, Barbro Dahlén, Mina Gaga, Mark Gjomarkaj, Peter H Howarth, Sebastian L Johnston, Guy F Joos, Frank Kanniess, Eleni Tzortzaki, Anna James, Roelinde J M Middelveld, Sven-Erik Dahlén
Journal: Thorax (2013)

<h3>Background</h3> Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. <h3>Methods</h3> In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. <h3>Results</h3> Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥3%, body mass index &gt;25 and low quality of life (St George9s Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p&lt;0.05). <h3>Conclusions</h3> Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.
Resistance to TRAIL Is Mediated by DARPP-32 in Gastric Cancer
Authors: Abbes Belkhiri, Shoumin Zhu, Zheng Chen, Mohammed Soutto, Wael El-Rifai
Journal: Clinical Cancer Research (2012)

Dopamine and cAMP-regulated phosphoprotein, Mr 32,000 (DARPP-32), is overexpressed during the gastric carcinogenesis cascade. Here, we investigated the role of DARPP-32 in promoting resistance to treatment with TRAIL.In vitro cell models including stable expression and knockdown of DARPP-32 were used. The role of DARPP-32 in regulating TRAIL-dependent apoptosis was evaluated by clonogenic survival assay, Annexin V staining, immunofluorescence, quantitative reverse transcriptase PCR, Western blot, and luciferase reporter assays.Stable expression of DARPP-32 in MKN-28 cells enhanced cell survival and suppressed TRAIL-induced cytochrome c release and activation of caspase-8, -9, and -3. Conversely, short hairpin RNA-mediated knockdown of endogenous DARPP-32 sensitized the resistant MKN-45 cells to TRAIL-induced apoptosis and enhanced TRAIL-mediated activation of caspase-8, -9, and -3. DARPP-32 induced BCL-xL expression through activation of Src/STAT3 signaling, and treatment with the Src-specific inhibitor PP1 abrogated DARPP-32-dependent BCL-xL upregulation and cell survival in MKN-28 cells. The TRAIL treatment induced caspase-dependent cleavage of NF-κBp65 protein; this cleavage was prevented by DARPP-32, thus maintaining NF-κB activity and the expression of its target, FLIP(S) protein. This suggests that upregulation of BCL-xL could play a possible role in blocking the mitochondria intrinsic apoptosis pathway, whereas the DARPP-32 effect on the NF-κB/FLIP(S) axis could serve as an additional negative feedback loop that blocks TRAIL-induced activation of caspase-8.Our findings uncover a novel mechanism of TRAIL resistance mediated by DARPP-32, whereby it inhibits the intrinsic apoptosis pathway through upregulation of BCL-xL, and the extrinsic apoptosis pathway through the NF-κB/FLIP(S) axis.
Consent Form Heterogeneity in Cancer Trials: The Cooperative Group and Institutional Review Board Gap
Authors: S. A. Koyfman, P. Agre, R. Carlisle, L. Classen, C. Cheatham, J. P. Finley, N. Kuhrik, M. Kuhrik, T. K. Mangskau, J. O'Neill, C. P. Reddy, E. Kodish, M. S. McCabe
Journal: JNCI Journal of the National Cancer Institute (2013)

Cooperative group (CG) provided consent forms (CGP-CFs) undergo re-review and revision by local institutional review boards (IRB) before institutional approval. We compared the relative readability and length of IRB-approved consent forms (IRB-CFs) used at seven academic institutions with their corresponding CGP-CFs. We also assessed the variability of these metrics across our institutions. This study included 197 consent forms (CFs) from 56 CG trials that were open in at least two of the participating institutions. The Flesch Reading Ease Score (FRES), the Flesch–Kincaid Grade Level (FKGL), and document length were collected on all CFs. Unpaired t test was used to compare length and readability of CGP-CF with the IRB-CF. Analysis of variance and Bonferroni-Dunn tests were used to assess interinstitutional variability in readability for all IRB-CFs. All statistical tests were two-sided. IRB-CFs were statistically significantly longer than CGP-CFs (mean number of pages = 17 vs 13; P < .001). Mean FKGLs were higher (10.3 vs 9.4; P < .0001) and the mean FRESs were lower (53.1 vs 57.1; P < .0001) for IRB-CFs compared with CGP-CFs. Readability varied statistically significantly between institutions for all sections of the IRB-CF ( P < .0001). Finalized IRB-CFs for identical clinical trials at different institutions demonstrated substantial heterogeneity of readability and length. As CFs progress from National Cancer Institute (NCI)–sponsored CGs to local IRBs, they seem to become longer and less readable. Interinstitutional heterogeneity in CF readability is substantial and widespread. More consistent adherence to CGP-CFs based on the newly revised NCI CF template with minimal modification by local IRBs should help simplify and standardize CFs used in cancer clinical trials.
Epicutaneous Immunotherapy Prevents from Induction of Anaphylaxis to Further Allergens
Authors: Pierre Henri Benhamou, Lucie Mondoulet, Vincent Dioszeghy, Mélanie Ligouis, Camille Plaquet, Véronique Dhelft, Emilie Puteaux, Christophe Dupont
Journal: Journal of Allergy and Clinical Immunology (2015)
Novel Role of HAX-1 in Ischemic Injury Protection Involvement of Heat Shock Protein 90
Authors: Chi Keung Lam, Wen Zhao, Wenfeng Cai, Elizabeth Vafiadaki, Stela M. Florea, Xiaoping Ren, Yong Liu, Nathan Robbins, Zhiguo Zhang, Xiaoyang Zhou, Min Jiang, Jack Rubinstein, W. Keith Jones, Evangelia G. Kranias
Journal: Circulation Research (2012)

Rationale: Ischemic heart disease is characterized by contractile dysfunction and increased cardiomyocyte death, induced by necrosis and apoptosis. Increased cell survival after an ischemic insult is critical and depends on several cellular pathways, which have not been fully elucidated. Objective: To test the hypothesis that the anti-apoptotic hematopoietic lineage substrate-1–associated protein X-1 (HAX-1), recently identified as regulator of cardiac Ca cycling, also may ameliorate cellular injury with an ischemic insult. Methods and Results: We report that cardiac ischemia/reperfusion injury is associated with significant decreases in HAX-1 levels ex vivo and in vivo. Accordingly, overexpression of HAX-1 improved contractile recovery, coupled with reduced infarct size, plasma troponin I level, and apoptosis. The beneficial effects were associated with decreased endoplasmic reticulum (ER) stress response through specific inhibition of the inositol-requiring enzyme (IRE-1) signaling pathway, including its downstream effectors caspase-12 and the transcription factor C/EBP homologous protein. Conversely, HAX-1 heterozygous-deficient hearts exhibited increases in infarct size and IRE-1 activity. The inhibitory effects of HAX-1 were mediated by its binding to the N-terminal fragment of the heat shock protein 90 (Hsp90). Moreover, HAX-1 sequestered Hsp90 from IRE-1 to the phospholamban–sarcoplasmic/endoplasmic reticulum calcium ATPase complex. The HAX-1 regulation was further supported by loss of IRE-1 inhibition in presence of the Hsp90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin. Conclusions: Cardiac ischemia-reperfusion injury is associated with decreases in HAX-1 levels. Consequently, overexpression of HAX-1 promotes cardiomyocyte survival, mediated by its interaction with Hsp90 and specific inhibition of IRE-1 signaling at the ER/sarcoplasmic reticulum.
Factors Influencing Discrepancies Between Premortem and Postmortem Diagnoses
Authors: Ron M. Battle
Journal: JAMA (1987)

A study of 2067 autopsies collected from 32 university and community hospitals of various sizes located throughout the United States showed the rate of discrepancies between premortem and postmortem diagnoses to be influenced by the type and size of hospital, the age and sex of the patient, and the disease responsible for the patient's death. Of equivocal or no influence were the length of the terminal hospitalization, the degree of clinical involvement in the case of the person responsible for establishing the discrepancy level, and the autopsy rate, at least as it applies to community hospitals. (<i>JAMA</i>1987:258:339-344)
Lionel Cyril Kreeger
Authors: M. S. L. Kreeger
Journal: BMJ (2013)

Lionel Cyril Kreeger was a well loved and respected psychiatrist and a prominent leading figure in psychoanalysis and group analysis. He was appointed consultant psychiatrist and psychotherapist at the Halliwick Hospital in 1965, where he worked closely with Dr Pat de Mare in establishing a therapeutic community culture employing small and large groups. He moved to …
CXCR4 expression heterogeneity in neuroblastoma cells due to ligand-independent regulation
Authors: Alex J Carlisle, Christopher A Lyttle, Rosalind Y Carlisle, John M Maris
Journal: Molecular Cancer (2009)

Abstract Background CXCR4, the receptor for the chemokine stromal-derived factor 1 (SDF-1), has been shown to mediate many of the processes essential for cancer progression such as tumor cell proliferation, metastasis, and angiogenesis. To understand the role of CXCR4 in the biology of neuroblastoma, a disease that presents with wide spread metastases in over 50% of patients, we screened ten patient derived-neuroblastoma cell-lines for basal CXCR4 expression and sought to identify characteristics that correlate with tumor cell phenotype. Results All cell lines expressed CXCR4 mRNA at variable levels, that correlated well with three distinct classes of CXCR4 surface expression (low, moderate, or high) as defined by flow cytometry. Analysis of the kinetics of CXCR4 surface expression on moderate and high expressing cell lines showed a time-dependent down-regulation of the receptor that directly correlated with cell confluency, and was independent of SDF1. Cell lysates showed the presence of multiple CXCR4 isoforms with three major species of approximately 87, 67 and 55 kDa associating with high surface expression, and two distinct species of 45 and 38 kDa correlating with low to null surface expression. Western blot analysis of CXCR4 immunoprecipitates showed that the 87 and 67 kDa forms were ubiquitinated, while the others were not. Finally, treatment of cells with a proteasome inhibitor resulted in down regulation of CXCR4 surface expression. Conclusions Taken together, these data show that regulation of CXCR4 surface expression in neuroblastoma cells can occur independently of SDF-1 contribution arguing against an autocrine mechanism. Additionally these data suggest that post-translational modifications of CXCR4, in part through direct ubiquitination, can influence trafficking of CXCR4 to the surface of neuroblastoma cells in a ligand-independent manner.
Reciprocal Activation of CD4+ T Cells and Synovial Fibroblasts by Stromal Cell–Derived Factor 1 Promotes RANKL Expression and Osteoclastogenesis in Rheumatoid Arthritis
Authors: Hae‐Rim Kim, Kyoung‐Woon Kim, Bo‐Mi Kim, Hong‐Geun Jung, Mi‐La Cho, Sang‐Heon Lee
Journal: Arthritis & Rheumatology (2013)

Objective Stromal cell–derived factor 1 (SDF‐1) is a chemokine that is involved in the bone‐destructive process in rheumatoid arthritis (RA) and bony metastasis in malignancy. This study was undertaken to determine the role and mechanism of SDF‐1 in RA‐associated osteoclastogenesis. Methods The expression of SDF‐1, tumor necrosis factor α (TNFα), and RANKL in RA synovial tissue was analyzed using confocal microscopy. After synovial fibroblasts and CD4+ T cells were treated with SDF‐1, RANKL messenger RNA expression was determined by real‐time and reverse transcription polymerase chain reaction. Osteoclastogenesis was assessed by counting tartrate‐resistant acid phosphatase–positive multinucleated cells in CD14+ monocytes cultured with SDF‐1 in the presence of anticytokine antibodies or signal inhibitors and in monocytes cocultured with SDF‐1–pretreated synovial fibroblasts and CD4+ T cells. Results RANKL, TNFα, and SDF‐1 were coexpressed in the lining and sublining of RA synovium. SDF‐1 stimulated RANKL expression in RA synovial fibroblasts and CD4+ T cells, and TNFα inhibition reduced this stimulation. When monocytes isolated from human peripheral blood were cultured with SDF‐1, they were differentiated into osteoclasts in the absence of RANKL. Monocytes were also differentiated into osteoclasts when they were cocultured with SDF‐1–pretreated synovial fibroblasts or CD4+T cells; however, this osteoclastogenesis was reduced by TNFα inhibition. Conclusion Our findings indicate that SDF‐1 induces osteoclastogenesis directly and indirectly via up‐regulating RANKL expression in RA synovial fibroblasts and CD4+ T cells, and that this is mediated by TNFα. The axis of SDF‐1 and RANKL is a potential therapeutic target for RA‐associated bone destruction.
Activation of macrophages in vivo and in vitro. Correlation between hydrogen peroxide release and killing of Trypanosoma cruzi.
Authors: C Nathan, N Nogueira, C Juangbhanich, J Ellis, Z Cohn
Journal: The Journal of Experimental Medicine (1979)

As reported previously, mouse peritoneal macrophages could be activated to kill intracellular trypomastigotes of Trypanosoma cruzi, the agent of Chagas' disease, in either of two ways: by immunizing and boosting the mice (3), or by culturing resident or inflammatory macrophages in spleen cell factor(s) (SCF) in vitro (2). Macrophages activated in vivo became less trypanocidal with time in culture, and cells activated in vitro lost trypanocidal capacity when CSF was removed (2). In the present study, the ability of macrophages to release H2O2 in response to phorbol myristate acetate (PMA) could be induced in vivo and in vitro, and reversed in vitro, in a manner correlating closely with changes in trypanocidal activity. Macrophages could be activated in vitro with SCF in a time-dependent and dose-dependent fashion, so that they released as much H2O2 as macrophages activated in vivo. The sensitivity of epimastigotes and trypomastigotes to enzymatically generated H2O2 suggested that the generation of H2O2 by activated macrophages could be plausible explanation for their trypanocidal activity. Of the biochemical correlates of macrophage activation reported to date, increased ability to release H2O2 seems most closely allied to enhanced capacity to kill an intracellular pathogen.
Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'
Authors: Leonid Bystrykh, Ellen Weersing, Bert Dontje, Sue Sutton, Mathew T Pletcher, Tim Wiltshire, Andrew I Su, Edo Vellenga, Jintao Wang, Kenneth F Manly, Lu Lu, Elissa J Chesler, Rudi Alberts, Ritsert C Jansen, Robert W Williams, Michael P Cooke, Gerald de Haan
Journal: Nature Genetics (2005)
A central mechanism of acute baroreflex resetting in the conscious dog.
Authors: W Tan, M J Panzenbeck, M A Hajdu, I H Zucker
Journal: Circulation Research (1989)

The role of the central nervous system in the mechanism(s) involved in acute carotid baroreflex resetting was studied in six conscious, chronically instrumented, aortic-denervated dogs. Dogs were prepared for reversible vascular isolation of the carotid sinuses. Acute baroreflex resetting was induced by holding the left carotid sinus pressure (LCcsp) at a given value for 20 minutes using a pulsatile pressure control system while at the same time keeping the right carotid sinus pressure (RCSP) at a subthreshold level (approximately 40 mm Hg). At the end of the 20 minutes, the LCcsp) was reduced to approximately 20 mm Hg, and a baroreflex (RCSP-mean arterial pressure [MAP]) curve was generated on the right carotid sinus using static-step increases in carotid sinus pressure. At the control LCcsp of 100 mm Hg, the RCSP-MAP baroreflex had a threshold pressure (Pth) of 86.6 +/- 3.1 mm Hg and a set point pressure (Psp) of 104.7 +/- 2.5 mm Hg. Increasing LCcsp) to 140 mm Hg for 20 minutes caused these parameters for the right carotid baroreflex to increase. Pth and Psp increased by 18.4 +/- 4.0 and 14.2 +/- 3.0 mm Hg, respectively (p less than 0.05). The baroreflex curve, therefore, was shifted upward and to the right. Decreasing LCcsp to 60 mm Hg caused Pth and Psp to decrease by 24.7 +/- 5.0 and 18.1 +/- 2 mm Hg, respectively (p less than 0.05). The baroreflex curve was therefore shift downward and to the left. The percent of resetting of Pth and Psp was 46 +/- 9% and 36 +/- 8%, respectively, when LCcsp was 140 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)
Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling
Authors: L. Gao, G. E. Mann
Journal: Cardiovascular Research (2009)

Oxidative stress mediated by hyperglycaemia-induced generation of reactive oxygen species (ROS) contributes significantly to the development and progression of diabetes and related vascular complications. NAD(P)H oxidase has been implicated as the major source of ROS generation in the vasculature in response to high glucose and advanced glycation end-products. Sustained activation of NAD(P)H oxidase in diabetes may diminish intracellular levels of NADPH, an essential cofactor for endothelial NO synthase (eNOS) and several antioxidant systems. Recent evidence suggests that basal ROS production via NAD(P)H oxidase may upregulate antioxidant enzyme defenses via redox signalling. Thus, NAD(P)H oxidase may serve as a double-edged sword, with transient activation providing a feedback defense against excessive ROS generation through the activation of receptor tyrosine kinases and the redox-sensitive Nrf2-Keap1 signalling pathway. Overproduction of ROS leads to eNOS uncoupling, mitochondrial dysfunction, and impaired antioxidant defenses owing to depletion of intracellular NADPH. Given the largely negative outcome of antioxidant therapy in the treatment of diabetic complications, targeting the redox-sensitive transcription factor Nfr2 may provide an effective strategy to restore antioxidant defenses in diabetes.
Protein Degradation by the Ubiquitin–Proteasome Pathway in Normal and Disease States
Authors: Stewart H Lecker, Alfred L Goldberg, William E Mitch
Journal: Journal of the American Society of Nephrology (2006)

The study was designed to assess the patterns of use of home mechanical ventilation (HMV) for patients with chronic respiratory failure across Europe. A detailed questionnaire of centre details, HMV user characteristics and equipment choices was sent to carefully identified HMV centres in 16 European countries. A total of 483 centres treating 27,118 HMV users were identified. Of these, 329 centres completed surveys between July 2001 and June 2002, representing up to 21,526 HMV users and a response rate of between 62% and 79%. The estimated prevalence of HMV in Europe was 6.6 per 100,000 people. The variation in prevalence between countries was only partially related to the median year of starting HMV services. In addition, there were marked differences between countries in the relative proportions of lung and neuromuscular patients using HMV, and the use of tracheostomies in lung and neuromuscular HMV users. Lung users were linked to a HMV duration of &lt;1 yr, thoracic cage users with 6–10 yrs of ventilation and neuromuscular users with a duration of ≥6 yrs. In conclusion, wide variations exist in the patterns of home mechanical ventilation provision throughout Europe. Further work is needed to monitor its use and ensure equality of provision and access.
High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel
Authors: D. Crivellari, O. Pagani, A. Veronesi, D. Lombardi, F. Nolè, B. Thürlimann, D. Hess, M. Borner, J. Bauer, G. Martinelli, R. Graffeo, C. Sessa, A. Goldhirsch
Journal: Annals of Oncology (2001)
Sex-Specific Chest Pain Characteristics in the Early Diagnosis of Acute Myocardial Infarction
Authors: Maria Rubini Gimenez, Miriam Reiter, Raphael Twerenbold, Tobias Reichlin, Karin Wildi, Philip Haaf, Katharina Wicki, Christa Zellweger, Rebeca Hoeller, Berit Moehring, Seoung Mann Sou, Mira Mueller, Kris Denhaerynck, Bernadette Meller, Fabio Stallone, Sarah Henseler, Stefano Bassetti, Nicolas Geigy, Stefan Osswald, Christian Mueller
Journal: JAMA Internal Medicine (2013)

Whether sex-specific chest pain characteristics (CPCs) would allow physicians in the emergency department to differentiate women with acute myocardial infarction (AMI) from women with other causes of acute chest pain more accurately remains unknown. OBJECTIVE To improve the management of suspected AMI in women by exploring sex-specific CPCs.From April 21, 2006, through August 12, 2012, we enrolled 2475 consecutive patients (796 women and 1679 men) presenting with acute chest pain to 9 emergency departments in a prospective multicenter study. The final diagnosis of AMI was adjudicated by 2 independent cardiologists.Treatment of AMI in the emergency department.Sex-specific diagnostic performance of 34 predefined and uniformly recorded CPCs in the early diagnosis of AMI.Acute myocardial infarction was the adjudicated final diagnosis in 143 women (18.0%) and 369 men (22.0%). Although most CPCs were reported with similar frequency in women and men, several CPCs were reported more frequently in women (P < .05). The accuracy of most CPCs in the diagnosis of AMI was low in women and men, with likelihood ratios close to 1. Thirty-one of 34 CPCs (91.2%) showed similar likelihood ratios for the diagnosis of AMI in women and men, and only 3 CPCs (8.8%) seemed to have a sex-specific diagnostic performance with P < .05 for interaction. These CPCs were related to pain duration (2-30 and >30 minutes) and dynamics (decreasing pain intensity). However, because their likelihood ratios were close to 1, the 3 CPCs did not seem clinically helpful. Similar results were obtained when examining combinations of CPCs (all interactions, P ≥ .05).Differences in the sex-specific diagnostic performance of CPCs are small and do not seem to support the use of women-specific CPCs in the early diagnosis of AMI. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00470587.