tbuckley/cabot-search huggingface dataset:
Annals Story Slam - Fallible
Authors: Vidya B. Viswanathan
Journal: Annals of Internal Medicine (2017)

Web Exclusives2 May 2017Annals Story Slam - FallibleFREEVidya B. Viswanathan, BAVidya B. Viswanathan, BAFrom Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0044 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Fallible "Fallible," by Vidya Viswanathan (Duration 6:41)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.Current Author Address: Vidya B. Viswanathan, BA, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; e-mail, vidya.[email protected]upenn.edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 2 May 2017Volume 166, Issue 9Page: SS1 ePublished: 2 May 2017 Issue Published: 2 May 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Erratum to: Disassembled DJ-1 high molecular weight complex in cortex mitochondria from Parkinson's disease patients
Authors: Zhenyu Zhong, Hikmet Nural, Ping He, Gina Civarella, Thomas Beach, Lucia Sue, Charles Adler, Holly Shill, John Caviness, Weiming Xia, Yong Shen
Journal: Molecular Neurodegeneration (2009)

Abstract Correction to Nural H, He P, Beach T, Sue L, Xia W, Shen Y. Disassembled DJ-1 high molecular weight complex in cortex mitochondria from Parkinson's disease patients Molecular Neurodegeneration 2009, 4:23.
Abstract 14867: Depression is a Major Predictor of Quality of Life in Adults Supported by a Left Ventricular Assist Device
Authors: Martha Abshire, Horng-Shiuann Wu, Jesus Casida
Journal: Circulation (2016)

Introduction: Anxiety and depression are prevalent in heart failure (HF). However, very little is known about the associations among anxiety, depression, and quality of life (QOL) in advanced HF pa...
Effect of Long-Term Metformin and Lifestyle in the Diabetes Prevention Program and Its Outcome Study on Coronary Artery Calcium
Authors: Ronald B. Goldberg, Vanita R. Aroda, David A. Bluemke, Elizabeth Barrett-Connor, Matthew Budoff, Jill P. Crandall, Dana Dabelea, Edward S. Horton, Kieren J. Mather, Trevor J. Orchard, David Schade, Karol Watson, Marinella Temprosa
Journal: Circulation (2017)

Despite the reduced incidence of coronary heart disease with intensive risk factor management, people with diabetes mellitus and prediabetes remain at increased coronary heart disease risk. Diabetes prevention interventions may be needed to reduce coronary heart disease risk. This approach was examined in the DPP (Diabetes Prevention Program) and the DPPOS (Diabetes Prevention Program Outcome Study), a long-term intervention study in 3234 subjects with prediabetes (mean±SD age, 64±10 years) that showed reduced diabetes risk with lifestyle and metformin compared with placebo over 3.2 years.
Molecular epidemiological prospective study of <i>EGFR</i> mutations from Asian patients (pts) with advanced lung adenocarcinoma (PIONEER).
Authors: Pan-Chyr Yang, Yuankai Shi, Joseph Siu-kie Au, Sankar Srinivasan, Gerardo H. Cornelio, Chun-Ming Tsai, Sumitra Thongprasert, Dr Karin Heeroma, Itoh Yohji, Mai Trong Khoa
Journal: Journal of Clinical Oncology (2012)

1534 Background: The epidemiological, multicenter prospective study (NCT01185314; PIONEER) assessed EGFR mutation (M) rates in pts from Asia with newly diagnosed advanced lung adenocarcinoma (ADC). Influence of demographic and clinical factors on EGFR M rates was investigated. Methods: Pts were aged ≥20 years, with treatment naïve stage IIIB/IV lung ADC. Tumor sample (biopsy, surgical specimen, cytology) EGFR M status (primary endpoint; positive [M+], negative [M-], undetermined [MU]) was determined using Scorpion ARMS (Therascreen EGFR RGQ kit). EGFR M frequency was calculated and compared between demographic/clinical factor subgroups (chi-square/Fisher’s exact test). Factors with p&lt;0.05 in the univariate analysis were further analyzed by multivariate logistic regression at 1% significance level to take the large dataset into consideration. Results: Of 1482 pts from 7 Asian countries, 43.4% were female, mean age was 60 years (range 17-94), and 52.6% were never-smokers. EGFR M status was evaluated in 1450 patients (32 [2.2%] were MU): 746 (51.4%) were M+, 704 (48.6%) were M-. Country, gender, ethnicity, smoking status, pack years, metastasis, (all p&lt;0.001) and disease stage (p=0.009) correlated significantly with EGFR M status. EGFR M+ rate by country: Vietnam 64.2% (77/120), Taiwan 62.1% (108/174), Thailand 53.8% (63/117), Philippines 52.3% (34/65), China 50.2% (372/741), Hong Kong 47.2% (76/161), India 22.2% (16/72). EGFR M+ rates were 61.1% in females, 44.0% in males, 60.7% in never smokers, and 31.4% in heavy smokers (&gt;50 pack years). EGFR M+ rates were 37.5% in male regular smokers (113/301), 34.8% in female regular smokers (8/23), 56.5% in male never smokers (104/184) and 62.0% in female never smokers (358/577). Ethnic group (p&lt;0.001) and pack years (p&lt;0.001) were identified as important factors by logistic regression; gender was not significant when adjusted for smoking status. Conclusions: The overall EGFR M+ rate in unselected ADC was 51.4%. Ethnicity and pack years were found to have a statistically significant association with EGFR M rates. There was no association between gender and EGFR M rates when adjusted for smoking status.
NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain
Authors: Andrea Stutz, Carl-Christian Kolbe, Rainer Stahl, Gabor L. Horvath, Bernardo S. Franklin, Olivia van Ray, Rebecca Brinkschulte, Matthias Geyer, Felix Meissner, Eicke Latz
Journal: The Journal of Experimental Medicine (2017)

NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge–charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation.
Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis
Authors: Judith Simcox, Gisela Geoghegan, John Alan Maschek, Claire L. Bensard, Marzia Pasquali, Ren Miao, Sanghoon Lee, Lei Jiang, Ian Huck, Erin E. Kershaw, Anthony J. Donato, Udayan Apte, Nicola Longo, Jared Rutter, Renate Schreiber, Rudolf Zechner, James Cox, Claudio J. Villanueva
Journal: Cell Metabolism (2017)
Mortality in ANCA-associated vasculitis: ameta-analysis of observational studies
Authors: Ju Ann Tan, Natasha Dehghan, Wenjia Chen, Hui Xie, John M Esdaile, J Antonio Avina-Zubieta
Journal: Annals of the Rheumatic Diseases (2017)

Objective To determine the magnitude of all-cause mortality risk in patients with antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) compared with the general population through a meta-analysis of observational studies. Methods We searched Medline and Embase databases from their inception to April 2015. Observational studies that met the following criteria were assessed by two researchers: (1) clearly defined AAV identified by either the American College of Rheumatology 1990 classification criteria or the 2012 Chapel Hill Consensus Conference disease definitions, and (2) reported standardised mortality ratios (SMR) and 95% CI. We calculated weighted-pooled summary estimates of SMRs (meta-SMRs) for all-cause mortality using random-effects model, tested for publication bias and heterogeneity. Results Ten studies met the inclusion criteria, comprising 3338 patients with AAV enrolled from 1966 to 2009, and a total of 1091 observed deaths. Overall, we found a 2.7-fold increased risk of death in patients with AAV when compared with the general population (meta-SMR: 2.71 (95% CI 2.26 to 3.24)). Analysis on studies that included only granulomatosis with polyangiitis cases also indicated a similar mortality risk (meta-SMR: 2.63 (95% CI 2.02 to 3.43)). There was no significant publication bias or small-study effect. Subgroup analyses showed that mortality risks were higher in older cohorts, with a trend towards improvement over time (ie, those with their midpoint of enrolment periods that were between 1980–1993 and 1994–1999, vs 2000–2005). Conclusion Published data indicate there is a 2.7-fold increase in mortality among patients with AAV compared with the general population.
Transcatheter pancreatoscopy-guided electrohydraulic lithotripsy for large pancreatic duct stones
Authors: Yuji Hodo, Yukihiro Shirota, Tsuyoshi Suda, Tokio Wakabayashi
Journal: Endoscopy (2017)

A 61-year-old man was admitted for treatment of alcohol-related chronic pancreatitis with recurrent acute exacerbations. Computed tomography (CT) scanning showed a large cluster of stones in the main pancreatic duct of the head of the pancreas and upstream duct dilatation ([Fig. 1]). We used endoscopic retrograde cholangiopancreatography (ERCP) and pancreatoscopy with electrohydraulic lithotripsy (EHL) to reduce the patient’s stone burden and ductal hypertension. Pancreatoscopy was attempted using the SpyGlass Direct Visualization System with a SpyScope catheter (Boston Scientific, Natick, Massachusetts, USA), but the catheter was too large to pass through the duct without dilation. Therefore, we used a double-lumen catheter (Introducer of a CytoMax II Double Lumen Biliary Cytology Brush; Cook Medical, Winston-Salem, North Carolina, USA), which is smaller than the SpyScope catheter. A SpyGlass optical probe and an EHL probe (Walz Elektronik GmbH, Rohrdorf, Germany) could then be passed together through the lumen of the catheter.
EULAR recommendations underplay importance of severe anxiety and depression in fibromyalgia treatment
Authors: Cecilia Mercieca, Andrew A Borg
Journal: Annals of the Rheumatic Diseases (2017)

The European League Against Rheumatism recently published updated recommendations on the management of fibromyalgia (FM), including pharmacological and non-pharmacological measures.1 While non-pharmacological measures are now the first approach, there is no stratification according to severity of anxiety or depression prior to selecting treatment options.

We are concerned that these recommendations seriously underplay the role of the need of expert psychological and psychiatric assessment prior to the selection of treatment strategies. Severe anxiety and/or depression may prevent the ability to comply with non-pharmacological therapy such as exercise or cognitive behavioural therapy, and the interactions with chronic pain and fatigue can become cyclical and self-perpetuating. Additionally it is known in FM that …
Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma
Authors: Michael Olvedy, Julie C. Tisserand, Flavie Luciani, Bram Boeckx, Jasper Wouters, Sophie Lopez, Florian Rambow, Sara Aibar, Bernard Thienpont, Jasmine Barra, Corinna Köhler, Enrico Radaelli, Sophie Tartare-Deckert, Stein Aerts, Patrice Dubreuil, Joost J. van den Oord, Diether Lambrechts, Paulo De Sepulveda, Jean-Christophe Marine
Journal: Journal of Clinical Investigation (2017)

Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer.
Abstract P037: Viable Autologous Umbilical Cord Patch for Aortic Reconstruction in Newborn Piglets
Authors: James M Hammel, Haili Lang, Rebecca Siecke, Stan Radio
Journal: Circulation Research (2011)

Background: Aortic surgery in neonates often uses a patch of cryopreserved allogeneic artery. Drawbacks include alloimmunization in infants who may later need heart transplant. We hypothesized that the umbilical cord (UC) may be a non-immunogenic, viable vascular patch suited to neonatal aortic surgery. This was evaluated in ex vivo studies of human UC, and in vivo study in piglets. Method: Human UC (20) were collected after vaginal birth, were dilated and measured. Swab cultures were taken. For final culture UC was put in Thiol, and held for 4 wk. Disinfection was in dilute hypochlorite for 30 sec to 5 min. UC segments were stored in HTK solution with antibiotic/antifungal agent at 4 deg for 3 to 9 d. Samples were fixed for histology. At 9 d, samples were put in tissue culture to check viability. Then, 18 farm piglets in three litters were delivered by hysterotomy. Each UC was sanitized, cultured, and stored as described for human UC. At 7 d, each piglet underwent laparotomy. A defect made in the abdominal aorta was patched with autologous UC or with PTFE. Piglets were killed after 8 and 12 wk to examine the patched aorta. Result: Human UC diameter was 8-11 mm. Cultures of 5 UC in Dakins for 30 sec, 1, 2, 3, and 4 min were all negative. All later UC were treated for 30 sec only. One culture from one UC segment after 9 d was positive; final culture from this UC wwas negative. Histology did not differ at 9 d from day of delivery (n=3). Cells grew from 9 d UC in tissue culture (n=2). Piglet UC at 7 d also held viable cells. Piglet UC patch worked well in surgery. Hemostasis was rapid with UC, and was longer with PTFE. Three piglets were killed before 8 wk due to hernia. There was no dehiscence, infection, or aneurysm in either group. UC-patched aorta lengthened 114%, PTFE grew 21%. Patched aorta was non-stenotic in both groups, 92% of normal in UC vs. 95% in PTFE. By histology the UC did not remain viable, but calcified and broke into fragments. Beneath both UC and PTFE patches, fibroblast proliferation spanned the aortic defect. In UC piglets, this layer enlarged after UC fragmentation. Conclusion: UC can be sterilized and kept viable after vaginal birth . UC patch worked well for repair of an aortic defect in piglets, but UC viability and growth were not seen. UC needs further study before trial in human aortic surgery.
Abstract 339: DWORF: a Novel Cardiac Micropeptide That Enhances SERCA Activity and Cardiomyocyte Contractility
Authors: Catherine A Makarewich, Benjamin R Nelson, Austin L Reese, Benjamin R Winders, Douglas M Anderson, John R McAnally, Ege T Kavalali, Rhonda Bassel-Duby, Eric N Olson
Journal: Circulation Research (2015)

Background: Our lab has discovered a novel conserved micropeptide of 34 amino acids encoded by a muscle-specific RNA that was previously annotated as a putative long non-coding RNA (lncRNA). This micropeptide, which we named DWORF (DWarf Open Reading Frame), shares structural similarity with the known SERCA modulators phospholamban (PLN), sarcolipin (SLN) and myoregulin (MLN). Objective: To define the functional role of DWORF in the heart and elucidate its mechanism of action. Methods and Results: Immunofluorescence staining and imaging in isolated adult mouse cardiac myocytes indicates that DWORF specifically localizes to sarcoplasmic reticulum (SR) membranes where it co-localizes with SERCA. Co-IP experiments performed in COS or HEK cells co-transfected with DWORF and SERCA show that DWORF forms a stable complex with various SERCA isoforms. Further biochemical analysis indicates that DWORF binds to the same site on SERCA as PLN, and overexpression of DWORF is capable of competing with PLN for SERCA binding. Co-expression of GFP-tagged DWORF and PLN in the presence of SERCA followed by SERCA pull-down and GFP Western indicates that PLN and DWORF have similar affinities for SERCA binding. Transgenic mice with cardiac specific over-expression of DWORF show enhanced cellular contractility as evidenced by increased peak Ca2+ transient amplitude and faster cytosolic Ca2+ decay rates (reduced Tau values). Furthermore, Ca2+-dependent Ca2+-uptake assays performed in homogenates from DWORF transgenic and littermate control hearts show a statistically significant leftward shift of the Ca2+-dependence curve for SERCA indicating a higher affinity of SERCA for Ca2+. Intriguingly, DWORF expression is silenced in the heart in response to pathological calcineurin signaling, implicating this micropeptide in the cellular pathway for calcineurin action. Conclusions: We have identified a novel muscle-specific micropeptide, DWORF, which is expressed in the heart at high levels and has the capacity to bind SERCA and modulate its function to increase contractility in transgenic mice. Our findings provide exciting data in support of DWORF as a previously unrecognized endogenous SERCA activator that plays a role in cardiac contractility.
Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence
Authors: Ümmügülsüm Yesilöz, Elmar Kirches, Christian Hartmann, Johannes Scholz, Siegfried Kropf, Felix Sahm, Makoto Nakamura, Christian Mawrin
Journal: Neuro-Oncology (2017)

Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated.We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter.The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho-mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho-extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P < .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found.AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.
Cardiovascular and neuropsychiatric risks of varenicline and bupropion in smokers with chronic obstructive pulmonary disease
Authors: Daniel Kotz, Wolfgang Viechtbauer, Colin R Simpson, Onno C P van Schayck, Robert West, Aziz Sheikh
Journal: Thorax (2017)

<h3>Background</h3> Varenicline and bupropion are effective smoking cessation treatments, but there are concerns about their safety in smokers with COPD. <h3>Objective</h3> To investigate whether varenicline and bupropion are associated with serious adverse cardiovascular and neuropsychiatric events in smokers with COPD. <h3>Methods</h3> In a retrospective cohort study, we used data from 14 350 patients with COPD included in the QResearch database, which holds data from 753 National Health Service general practices across England. We identified patients with COPD who received a prescription of nicotine replacement therapy (NRT; N=10 426; reference group), bupropion (N=350) or varenicline (N=3574) in the period between January 2007 and June 2012. Patients were followed up for 6 months to compare incident cardiovascular (ie, ischaemic heart disease, stroke, heart failure, peripheral vascular disease and cardiac arrhythmias) and neuropsychiatric (ie, depression and self-harm) events using Cox proportional hazards models, adjusted for potential confounders. Propensity score analysis was used as an additional approach to account for potential confounding by indication. We also modelled the effects of possible unmeasured confounders. <h3>Results</h3> Neither bupropion nor varenicline showed an increased risk of adverse events compared with NRT. Varenicline was associated with a significantly reduced risk of heart failure (HR=0.56, 95% CI 0.34 to 0.92) and depression (HR=0.73, 95% CI 0.61 to 0.86). Similar results were obtained from the propensity score analysis. Modelling of unmeasured confounding provided additional evidence that an increased risk of these adverse events was very unlikely. <h3>Conclusion</h3> In smokers with COPD, varenicline and bupropion do not appear to be associated with an increased risk of cardiovascular events, depression or self-harm in comparison with NRT.