tbuckley/cabot-search huggingface dataset:
Abstract 3427: Foxo1-Induced Stimulation of Autophagy Contributes to Cardiac Atrophy
Authors: Nirmala Hariharan, Shiori Kyoi, Soichiro Usui, Junichi Sadoshima
Journal: Circulation (2008)

The Forkhead box-O (Foxo) family transcription factors mediate atrophy in both skeletal and cardiac muscles. Autophagy is a bulk degradation process, in which cytosolic proteins are sequestered by double membrane vesicles termed autophagosomes and degraded through lysosomes. Expression of Foxo1 is upregulated when the heart undergoes atrophy, such as during cardiac unloading. We hypothesized that Foxo1 increases autophagic flux, which in turn plays an essential role in mediating atrophy of cardiac myocytes. Adenovirus harboring Foxo1 (Ad-Foxo1) was transduced into neonatal rat ventricular myocytes (NRVMs). Foxo1 significantly reduced the cell size at baseline (−54%, p&lt;0.01) and in response to phenylephrine (−61%, p&lt;0.01) in NRVMs, consistent with the notion that Foxo1 stimulates atrophy in cardiac myocytes. Ad-Foxo1 increased LC3-II/LC3-I (3.3 fold vs Ad-LacZ, p&lt;0.01) as well as GFP-LC3 dots (the number of dots/cell, 2.5 fold vs Ad-LacZ, p&lt;0.05), established indicators of autophagy. Ad-Foxo1 significantly reduced protein expression of p62/SQSTM1 (−45% vs Ad-LacZ, p&lt;0.05), a protein degraded through autophagy. Ad-Foxo1 also increased the autophagic flux, as determined by LC3-II/LC3-I (LacZ 0.69, Foxo1 6.92) and accumulation of p62/SQSTM1 (LacZ 0.57, Foxo1 1.18) in the presence of 50μM leupeptin and 500μM PMSF, lysosomal protease inhibitors. Both 3-methyladenine (3MA) and adenovirus harboring shRNA Beclin1 reduced both Foxo1-induced increases in LC3-II formation (LacZ 1.0, Foxo1 3.6, Foxo1+3MA 1.7, Foxo1+shBeclin1 1.3) and Foxo1-induced decreases in p62/SQSTM1, confirming that 3MA and shBeclin1 attenuate Foxo1-induced autophagy. Both 3MA and shRNA Beclin1 attenuated Foxo1 induced reduction in NRVM cell size (LacZ 100%; Foxo1 66%; Foxo1+3MA 81%, p&lt;0.05; Foxo1+shBeclin1 89%, p&lt;0.05) and the relative protein content (Foxo1+3MA vs Foxo1 p&lt;0.05; Foxo1+shBeclin1 vs Foxo1 p&lt;0.01), suggesting that that Foxo1-induced reduction in cell size is in part mediated by autophagy. In conclusion, these results suggest that Foxo1 stimulates autophagy in cardiac myocytes and that stimulation of the autophagy-lysosomal pathway plays an important role in mediating Foxo1-induced cardiac atrophy.
Gene expression profiles of normal human lung cells affected by adenoviral E1B
Authors: Xiao-Mei Rao, Xinyu Zheng, Sabine Waigel, Wolfgang Zacharias, Kelly M. McMasters, Heshan S. Zhou
Journal: Cancer Research (2006)

2993   Adenoviruses with deletion of E1B gene can selectively replicate in cancer cells. The underlying mechanisms in tumor selective replication of E1B-deleted adenoviruses are insufficiently understood. Identifying genes with altered expression patterns caused by the E1B proteins in virus-infected cells will further increase our understanding of E1B functions and provide insight into the tumor-selective replication of E1B-mutated adenoviruses on the molecular level. An approach based on large-scale gene array was applied to analyze molecular changes affected by viral E1B. We identified a total of 345 genes with expression changes of two-fold or greater affected by wild-type adenovirus compared with its E1B-deleted counterpart. E1B proteins affect the expression of a diverse range of genes, including CDC25A and cyclin E involved in cell cycle regulation, BCL-2 in apoptosis, heat shock 70K protein in stress responses, and vascular endothelial growth factor in angiogenesis and transcription. These results were confirmed by quantitative real-time PCR and Western blot. This is the first study of the global profile of gene expression altered by the virus E1B in human lung cells, and the majority of the genes were previously not known to be affected by the E1B proteins. The data presented in this study will lead to more detailed analysis of E1B functions and may also lead to development of new agents and approaches for oncolytic therapy.
Validation of FEV1 spirometric endpoints as a measure of the anti-inflammatory and bronchodilatory effects of fluticasone/formoterol combination therapy
Authors: Sanjeeva Dissanayake, Birgit Grothe, Tammy McIver, Kirsten Kaiser
Journal: European Respiratory Journal (2013)

Background:  The change from pre-dose FEV 1  at day 1 to 2-hours post-dose FEV 1  at week 12 was used as a co-primary spirometric outcome in the development of fluticasone/formoterol combination therapy (FLUT/FORM;  flutiform ®) in the pivotal studies. As this endpoint is not well characterised in the literature, we investigated its utility by examining the relationship with other spirometric and non-spirometric indices, including the change from pre-dose FEV 1  at day 1 to pre-dose FEV 1  at week 12 and FEV 1  AUC 0-12  at week 12 (area under the FEV 1  curve over 0-12 hrs post-dose at week 12).   Methods:  FEV 1  and AUC endpoint data from 3 randomised, double-blind, 12-week studies comparing FLUT/FORM pMDI to fluticasone pMDI were pooled, and Pearson’s correlation coefficient (R) or odds ratios were calculated.   Results and Conclusions:  Change from pre-dose FEV 1  at day 1 to 2h post-dose FEV 1  at week 12 assesses both chronic ICS-mediated anti-inflammatory and acute LABA bronchodilatory effects. This endpoint correlated well with the pre-dose FEV 1  (R=0.86) and FEV 1  AUC 0-12  (R=0.96) endpoints. Pre dose FEV 1  and 2h post-dose FEV 1  were similarly predictive of subsequent exacerbation risk. Both endpoints also exhibited similar correlations with other endpoints, e.g., asthma control days. These data indicate that 2h post-dose FEV 1  is a useful surrogate for FEV 1  AUC 0-12  in ICS-LABA vs ICS studies, and allows similar conclusions to be drawn as with pre-dose FEV 1 . Given greater treatment differences vs ICS, change from pre-dose FEV 1  at day 1 to 2h post-dose FEV 1  allows sample size savings in such studies if used as a primary endpoint instead of pre-dose FEV 1 .
Aberrant Epidermal Growth Factor Receptor Signaling and Enhanced Sensitivity to EGFR Inhibitors in Lung Cancer
Authors: Joseph Amann, Shailaja Kalyankrishna, Pierre P. Massion, Joyce E. Ohm, Luc Girard, Hisayuki Shigematsu, Michael Peyton, Denise Juroske, Yuhui Huang, J. Stuart Salmon, Young H. Kim, Jonathan R. Pollack, Kiyoshi Yanagisawa, Adi Gazdar, John D. Minna, Jonathan M. Kurie, David P. Carbone
Journal: Cancer Research (2005)

Epidermal growth factor receptor (EGFR) is occasionally amplified and/or mutated in non-small cell lung cancer (NSCLC) and can be coexpressed with other members of the HER receptor family to form functional heterodimers. We therefore investigated lung cancer cell lines for alterations in EGFR gene copy number, enhanced expression of EGFR and other HER family members, and EGFR coding sequence mutations and correlated these findings with response to treatment with the EGFR inhibitors and the kinetics of ligand-induced signaling. We show here that somatic deletions in the tyrosine kinase domain of EGFR were associated with increased EGFR gene copy number in NSCLC. Treatment with the specific EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib or the EGFR inhibitory antibody cetuximab induced apoptosis of HCC827, a NSCLC cell line with EGFR gene amplification and an exon 19 deletion. H1819, a NSCLC cell line that expresses high levels of EGFR, ErbB2, and ErbB3 but has wild-type EGFR, showed intermediate sensitivity to TKIs. In both cell lines, ligand-induced receptor tyrosine phosphorylation was delayed and prolonged and AKT was constitutively phosphorylated (but remained inhibitable by EGFR TKI). Thus, in addition to EGFR mutations, other factors in NSCLC cells, such as high expression of ErbB family members, may constitutively activate AKT and sensitize cells to EGFR inhibitors.
Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease
Authors: Maartje I. Kester, Charlotte E. Teunissen, Daniel L. Crimmins, Elizabeth M. Herries, Jack. H. Ladenson, Philip Scheltens, Wiesje M. van der Flier, John C. Morris, David M. Holtzman, Anne M. Fagan
Journal: JAMA Neurology (2015)

Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse.To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD).Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic-based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64 [2] years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68 [1] years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65 [1] years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014.Levels of NGRN in CSF samples.Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P < .001), but not with Aβ42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90 [45] pg/mL per year; P < .05) but not in patients with MCI or AD.Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss.
Fractional Flow Reserve to Determine the Appropriateness of Angioplasty in Moderate Coronary Stenosis
Authors: G. Jan Willem Bech, Bernard De Bruyne, Nico H.J. Pijls, Ebo D. de Muinck, Jan C.A. Hoorntje, Javier Escaned, Pieter R. Stella, Eric Boersma, Jozef Bartunek, Jacques J. Koolen, William Wijns
Journal: Circulation (2001)

Background —PTCA of a coronary stenosis without documented ischemia at noninvasive stress testing is often performed, but its benefit is unproven. Coronary pressure–derived fractional flow reserve (FFR) is an invasive index of stenosis severity that is a reliable substitute for noninvasive stress testing. A value of 0.75 identifies stenoses with hemodynamic significance. Methods and Results —In 325 patients for whom PTCA was planned and who did not have documented ischemia, FFR of the stenosis was measured. If FFR was &gt;0.75, patients were randomly assigned to deferral (deferral group; n=91) or performance (performance group; n=90) of PTCA. If FFR was &lt;0.75, PTCA was performed as planned (reference group; n=144). Clinical follow-up was obtained at 1, 3, 6, 12, and 24 months. Event-free survival was similar between the deferral and performance groups (92% versus 89% at 12 months and 89% versus 83% at 24 months) but was significantly lower in the reference group (80% at 12 months and 78% at 24 months). In addition, the percentage of patients free from angina was similar between the deferral and performance groups (49% versus 50% at 12 months and 70% versus 51% at 24 months) but was significantly higher in the reference group (67% at 12 and 80% at 24 months). Conclusions —In patients with a coronary stenosis without evidence of ischemia, coronary pressure–derived FFR identifies those who will benefit from PTCA.
Abstract 9923: The Ethics of Unilateral ICD and CRT-D Deactivation: Patient Perspectives
Authors: Margaret G Daeschler, Ralph J Verdino, James N Kirkpatrick
Journal: Circulation (2014)

Background: Decisions about deactivation of implantable cardioverter defibrillators (ICDs) are complicated. Unilateral Do-Not-Resuscitate (DNR) orders (against patient/family wishes) have been ethically justified in cases of medical futility. Unilateral deactivation of ICDs may be seen as a logical extension of a unilateral DNR order. Methods: 60 respondents who had an ICD or cardiac resynchronization therapy ICD (CRT-D) were interviewed at a quaternary medical center outpatient electrophysiology practice. Survey questions addressed the inclusion of ICD deactivation in advanced directives, whether ICD deactivation constitutes physician-assisted suicide, and whether unilateral ICD deactivation can be ethically justified. The average age was 59 (range 23-89), and 70% were male. Of the respondents, 35% had ICDs, and 65% had CRT-Ds. Respondents had had their devices for an average of 6.74 years (range 0.11-25). 82% of respondents were Caucasian, 15% were African American and 3% were Hispanic. Results: Only 15% of patients had thought about device deactivation if they were to develop a serious illness from which they were not expected to recover, and single respondents were more likely to have considered this point (38%, p=0.03). A small majority (53%) had advance directives, and only one mentioned what to do with the device. Only 3% had discussed device management with clinicians. Most (55%) believed turning off a patient’s pacemaker was no different than not performing CPR or administering external defibrillation. A majority (77%) did not consider device deactivation in accordance with patient wishes to be physician-assisted suicide. A majority (78%) responded that it was not ethical/moral for doctors to deactivate ICDs against patients’ wishes. Conclusion: In an era of cost-consciousness and scrutiny of resources, management of ICDs and CRT-Ds as patients near the end of their lives create ethical dilemmas. Few patients consider device deactivation at end of life, though a large majority believes that unilateral deactivation is not ethical or moral, even in the setting of medical futility. Advance care planning for these patients should address device deactivation.
Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells: possible involvement of STAT3 degradation by proteasome pathway in interleukin 6-dependent hematopoietic cells
Authors: Hanako Daino, Itaru Matsumura, Koji Takada, Junko Odajima, Hirokazu Tanaka, Shuji Ueda, Hirohiko Shibayama, Hirokazu Ikeda, Masahiko Hibi, Takashi Machii, Toshio Hirano, Yuzuru Kanakura
Journal: Blood (2000)
2-chlorodeoxyadenosine (cda) Therapy in Advanced Chronic Lymphocytic-leukemia (cll) and in Waldenstroms Macroglobulinemia (wm)
Authors: André Delannoy, Augustin Ferrant, P. Martiat, L. Montfort, Chantal Doyen, G. Sokal, Jl. Michaux
Journal: Blood (1993)
Efficacy and Safety of Pyridoxal 5′-Phosphate (MC-1) in High-Risk Patients Undergoing Coronary Artery Bypass Graft Surgery
Authors: John H Alexander, Robert W Emery, Michel Carrier, Stephen J Ellis, Rajendra H Mehta, Vic Hasselblad, Philippe Menasche, Ahmad Khalil, Robert Cote, Elliott Bennett-Guerrero, Michael J Mack, Gerhard Schuler, Robert A Harrington, Jean-Claude Tardif
Journal: JAMA (2008)

Coronary artery bypass graft (CABG) surgery is frequently performed and effective; however, perioperative complications related to ischemia-reperfusion injury, including myocardial infarction (MI), remain common and result in significant morbidity and mortality. MC-1, a naturally occurring pyridoxine metabolite and purinergic receptor antagonist, prevents cellular calcium overload and may reduce ischemia-reperfusion injury. Phase 2 trial data suggest that MC-1 may reduce death or MI in high-risk patients undergoing CABG surgery.To assess the efficacy and safety of MC-1 administered immediately before and for 30 days after surgery in patients undergoing CABG surgery.The MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery II Trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial, with 3023 intermediate- to high-risk patients undergoing CABG surgery with cardiopulmonary bypass enrolled between October 2006 and September 2007 at 130 sites in Canada, the United States, and Germany.Patients received either MC-1, 250 mg/d (n = 1519), or matching placebo (n = 1504) immediately before and for 30 days after CABG surgery.The primary efficacy outcome was cardiovascular death or nonfatal MI, defined as a creatine kinase (CK) MB fraction of at least 100 ng/mL or new Q waves through postoperative day 30.The primary efficacy outcome occurred in 140 of 1510 patients (9.3%) in the MC-1 group and 133 of 1486 patients (9.0%) in the placebo group (risk ratio, 1.04; 95% confidence interval, 0.83-1.30; P = .76). All-cause mortality was higher among patients assigned to MC-1 than placebo at 4 days (1.0% vs 0.3%; P = .03) but was similar at 30 days (1.9% vs 1.5%; P = .44). There was no difference in the 8- to 24-hour CK-MB area under the curve between the MC-1 and placebo groups (median, 270 [interquartile range, 175-492] vs 268 [interquartile range, 170-456] hours x ng/mL; P = .11).In this population of intermediate- to high-risk patients undergoing CABG surgery, MC-1 did not reduce the composite of cardiovascular death or nonfatal MI.clinicaltrials.gov Identifier: NCT00402506
Progress toward measles, elimination - European region, 2005-2008.
Authors: R. Martin, S. Deshevoi, D. Jankovic, A. Goel, D. Mercer, E. Laurent, A. Dabbagh, P. Strebel, N. Khetsuriani, S. Wassilak, A. Uzicanin
Journal: MMWR Morbidity and Mortality Weekly Report (2009)
On the Path to Global Open Access: A Few More Miles to Go
Journal: PLoS Medicine (2011)

The PLoS Medicine Editors' individual competing interests are at http://www.plosmedicine.org/static/editorsInterests.action. PLoS is funded partly through manuscript publication charges, but the PLoS Medicine Editors are paid a fixed salary (their salary is not linked to the number of papers published in the journal).



The PLoS Medicine Editors are each paid a salary by the Public Library of Science, and they wrote this editorial during their salaried time. No specific funding was received for this paper.



Provenance: Written by editorial staff; not externally peer reviewed.
The Impact of Transplant in AML in 2nd CR: A Prospective Study of 741 in the MRC AML 10 and 12 Trials.
Authors: Alan K. Burnett, Robert K. Hills, Anthony H. Goldstone, Donald Milligan, Archie G. Prentice, Ian Hann, David Webb, Brenda Gibson, Keith Wheatley
Journal: Blood (2004)
Obesity and asthma symptoms in children
Authors: Francisco-Javier Gonzalez-Barcala, Sonia Pértega, Juan Sánchez Lastres, Miguel Angel San José Gonzalez, Luis Bamonde, Luciano Garnelo, Teresa Pérez Castro, Manuel Sampedro, Luis Valdes, José-Manuel Alvarez-Dobaño, Lucía Ferreiro, Angel López Silvarrey
Journal: European Respiratory Journal (2012)

INTRODUCTION: The relationship between obesity and asthma show inconsistent results.  The purpose of our study was to evaluate the prevalence of asthma according to obesity in a large sample of the child population in our region (total population 2795422).  METHODS: A cross-sectional study, following the ISAAC study methodology, was conducted on randomly selected 6-7 year old children.  The asthma symptoms, demographic characteristics, and other potential risk factors were determined from the questionnaire. Overweight and obesity were defined based on the body mass index.  Multiple logistic regression were used to obtain adjusted prevalence odds ratios (OR) and 95% confidence intervals (95% CI) between asthma symptoms and obesity.  RESULTS: Finally, 7485 children were included (50.8% female).  Our results shown that 23.4% of our children were overweight, and 9.6% were obese.  The prevalence of wheezing ever was 39.0%, that of current asthma 13.5%, severe asthma 4.9%, and exercise induced asthma 6.4%.  Obesity was associated with an increase in the probability of wheezing ever (OR: 1.35) and exercise induced asthma (OR: 1.62).  CONCLUSION: In our population, obesity was associated with a higher prevalence of asthma in young children.
Specific sensitization to animals is an important risk factor for asthma in older age
Authors: Katja Warm, Linnea Hedman, Anne Lindberg, Bo Lundbäck, Eva Rönmark
Journal: European Respiratory Journal (2014)

Background:  Data on the impact of allergic sensitization on asthma and allergic rhinitis among elderly is rare.   Aim:  To assess the impact of allergic sensitization on asthma and allergic rhinitis in relation to age.   Methods:  A random population sample in ages 22-82 years was examined with structured interview and blood sampling for specific IgE for ten common airborne allergens. Of 1016 invited, 692 (68%) subjects participated in blood sampling. IgE ≥ 0.35 U/ml to the specific allergens was defined as a positive test.   Results:  Sensitization to both any allergen and specific allergens decreased with increasing age among subjects with asthma, allergic rhinitis and concomitant condition. Further, the prevalence of allergic sensitization among asthmatics decreased with increasing age of asthma onset, 86% with asthma onset ≤6 y, 56% between 7 and 19 y, 26% with asthma onset ≥20 y. In asthmatics ≥61 y, 22% were sensitized to any allergen, all of which were sensitized to cat, dog or horse. In subjects ≥61 y with allergic rhinitis, 27% were sensitized to any allergen, 20% to pollen, and 18% to animal. When the analysis was stratified for age and adjusted for confounders, sensitization to animal was stronger associated with asthma in ages ≥61y, OR 6.78 (95% CI 2.09-21.99) compared to subjects ≤40y, OR 3.96 (1.41-11.15). An inverse pattern was seen for allergic rhinitis.   Conclusion:  Although the overall impact of allergic sensitization on asthma and allergic rhinitis decreased with increasing age, the impact of sensitization to animal remained significant for asthma among elderly. Allergic sensitization has its strongest impact in asthmatics with early onset of asthma.
New US act overturns legality of doctor assisted suicide in Oregon
Authors: Fred Charatan
Journal: BMJ (1999)

Last month the US House of Representatives passed the Pain Relief Promotion Act, which effectively supersedes the state of Oregon's 1997 Death with Dignity Act. The Senate version, introduced by Senator Don Nickles and 31 cosponsors, seems also likely to pass.

Oregon is the only US state where doctor assisted suicide is legal. It allows voluntary self administration of lethal drugs expressly prescribed by a doctor for that purpose. It prohibits euthanasia—whereby a doctor directly administers a drug to end another person's life.

The new federal law's …