tbuckley/cabot-search huggingface dataset:
Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells
Authors: Ross D. Carruthers, Shafiq U. Ahmed, Shaliny Ramachandran, Karen Strathdee, Kathreena M. Kurian, Ann Hedley, Natividad Gomez-Roman, Gabriela Kalna, Mathew Neilson, Lesley Gilmour, Katrina H. Stevenson, Ester M. Hammond, Anthony J. Chalmers
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem–like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA-damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133− non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double-strand breaks, which colocalized with “replication factories” and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (&amp;gt;1 Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro. These data identify RS as a cancer stem cell–specific target with significant clinical potential. Significance: These findings shed new light on cancer stem cell biology and reveal novel therapeutics with the potential to improve clinical outcomes by overcoming inherent radioresistance in GBM. Cancer Res; 78(17); 5060–71. ©2018 AACR.
Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study
Authors: A.R. Hansen, C. Massard, P.A. Ott, N.B. Haas, J.S. Lopez, S. Ejadi, J.M. Wallmark, B. Keam, J.-P. Delord, R. Aggarwal, M. Gould, P. Yang, S.M. Keefe, S.A. Piha-Paul
Journal: Annals of Oncology (2018)

BackgroundPatients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented.Materials and methodsKey eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review.ResultsMedian patient age in this cohort (n= 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%–38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n= 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred.ConclusionPembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1–positive prostate cancer, and its side effect profile was favorable.ClinicalTrials.gov IdentifierNCT02054806
INTRODUCING AND IMPLEMENTING COLORECTAL ENDOSCOPIC SUBMUCOSAL DISSECTION IN WESTERN SETTING WITH HIRING JAPANESE SUPERVISOR
Authors: S Yamamoto, M Shafazand, T Radomski
Journal: Endoscopy (2018)

As compared to Japan, in Western countries with less endoscopic submucosal dissection (ESD) experts and less gastric neoplasms, it's difficult to introduce colorectal ESD (CR-ESD). We assessed the feasibility of introducing and implementing CR-ESD with hiring Japanese expert as a supervisor in Western setting.
Reply to D’Alessandro-Gabazza <i>et al.</i>: Risks of Treating Idiopathic Pulmonary Fibrosis with a TAM Receptor Kinase Inhibitor
Authors: Milena S. Espindola, David M. Habiel, Cory M. Hogaboam
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

We are most grateful for the letter provided by D'Alessandro-Gabazza and colleagues, in which they noted that our work represents a first step in the further development of a novel therapy in idiopathic pulmonary fibrosis (IPF), but they also expressed concerns around the targeting of TAM (Tyro3, Axl, Mer) receptors in this disease.The concerns expressed are well warranted; we share these concerns with the authors and are currently addressing them in our laboratory.Given the importance of alveolar epithelial health in the regeneration of the lung, we have been actively determining the effects of TAM receptors on epithelial cells in human lung tissues.Immunohistochemical analysis showed active Axl immunostaining by epithelial-like cells lining the honeycomb and adjacent to fibroblastic foci in IPF lung samples (1).However, this analysis did not specifically identify what epithelial subtype(s) are expressing this receptor.Mining of data produced by transcriptomic analysis of single epithelial cell RNA-Seq data sets (2-4) revealed that Axl was the only TAM receptor that was highly expressed (i.e., average transcripts per kilobase million expression) by human indeterminate, basal, and club/goblet epithelial cells (Figure 1, top left).However, these epithelial cell types rarely expressed Mertk (Figure 1, top right), Tyro3 (Figure 1, bottom left), and Gas6 (Figure 1, bottom right) transcripts.In addition, alveolar type 2 (AT2) cells express markedly lower Axl transcript compared with the other lung epithelial cell types, and Gas6, Tyro3, and Mertk transcripts were rarely detected in these cells (Figure 1).Our preliminary and unpublished single-cell RNA-Seq analysis of cultured-expanded IPF KRT5 1 basal and SCGB1A1 1 club epithelial cells supported
Letter by Calabrò et al Regarding Article, “Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk)”
Authors: Paolo Calabrò, Felice Gragnano, Arturo Cesaro
Journal: Circulation (2018)
Abstract 19760: Factors Influencing Blood Pressure Control and Therapeutic Adherence in a Comprehensive Hypertension Management Program
Authors: Daniela Sandoval, Miguel Bravo, Tomás Romero, Elard Koch, Jhonny Acevedo, Oscar HenrÍquez
Journal: Circulation (2012)

Background: Lack of life style modification counseling, poor antihypertensive drug therapy (Rx) adherence, low education, poor patient-physician relation have been described among other social determinants as hurdles in achieving blood pressure (BP) control in hypertensive patients. Objectives: This study assesses these factors in a government sponsored Cardiovascular Health Program (CHP) that provides free access to antihypertensive treatment and life style modification counseling to Chilean hypertensive population. Methods: From a universe of 1,512 hypertensive patients (1,069 women) between 30 y 68 years followed throughout the CHP, a sample of 349 patients was analyzed. All patients received free Rx and life style modifying counseling. Surveys of physician-patient relationship, weekly physical activity (leisure physical activity) family income and education level were carried out. Rx adherence was determined using the Morisky-Green-Levine test. Odds ratio (OR) analysis adjusted for age and sex was performed to assess the influence of these factors in BP control (&lt;140/90 mmHg) and Rx adherence. Results: The mean age of the sample was 55.0 ± 8.2 years. BP control was achieved in 49.0% (741 of 1,512) of patients. 94,5% (1,429 of 1,512) received pharmacological treatment. Adherence to antihypertensive Rx was 34.9% (499 of 1,429). Factors related to BP control and influencing Rx adherence with their OR are shown in Table 1. Conclusions: Education, patient-physician relation, low social support and physical activity level influenced BP control. The same factors with the exception of physical activity level influenced Rx adherence that did not appear to affect decisively BP control. These results underscore the importance of social determinants and life style modification counseling implemented throughout this comprehensive hypertension management in the Chilean CHP.
OPTICAL ENHANCEMENT TECHNOLOGY AS A DIAGNOSTIC TOOL IN PATIENTS WITH GASTROESOPHAGEAL REFLUX DISEASE
Authors: T Thomaidis, F Rahman, F Thieringer, G Tontini, K Mönkenmüller, I Sauid, P Galle, H Neumann
Journal: Endoscopy (2018)

Optical Enhancement technology (OE) combines optical filters with digital postprocessing for enhanced visualization of surface and vascular changes. This is the first study assessing the new technology for diagnosis of gastroesophageal reflux disease (GERD). Aim of this study is to investigate the utility of OE in improving the diagnosis of patients with GERD.
Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI
Authors: Ali C.M. Johnson, Richard A. Zager
Journal: Journal of the American Society of Nephrology (2018)

Background Recent clinical data support the utility/superiority of a new AKI biomarker (“NephroCheck”), the arithmetic product of urinary TIMP × IGFBP7 concentrations. However, the pathophysiologic basis for its utility remains ill defined. Methods To clarify this issue, CD-1 mice were subjected to either nephrotoxic (glycerol, maleate) or ischemic AKI. Urinary TIMP2/IGFBP7 concentrations were determined at 4 and 18 hours postinjury and compared with urinary albumin levels. Gene transcription was assessed by measuring renal cortical and/or medullary TIMP2/IGFBP7 mRNAs (4 and 18 hours after AKI induction). For comparison, the mRNAs of three renal “stress” biomarkers (NGAL, heme oxygenase 1, and p21) were assessed. Renal cortical TIMP2/IGFBP7 protein was gauged by ELISA. Proximal tubule–specific TIMP2/IGFBP7 was assessed by immunohistochemistry. Results Each AKI model induced prompt (4 hours) and marked urinary TIMP2/IGFBP7 increases without an increase in renal cortical concentrations. Furthermore, TIMP2/IGFBP7 mRNAs remained at normal levels. Endotoxemia also failed to increase TIMP2/IGFBP7 mRNAs. In contrast, each AKI model provoked massive NGAL, HO-1, and p21 mRNA increases, confirming that a renal “stress response” had occurred. Urinary albumin rose up to 100-fold and strongly correlated ( r =0.87–0.91) with urinary TIMP2/IGFBP7 concentrations. Immunohistochemistry showed progressive TIMP2/IGFBP7 losses from injured proximal tubule cells. Competitive inhibition of endocytic protein reabsorption in normal mice tripled urinary TIMP2/IGFBP7 levels, confirming this pathway’s role in determining urinary excretion. Conclusions AKI-induced urinary TIMP2/IGFBP7 elevations are not due to stress-induced gene transcription. Rather, increased filtration, decreased tubule reabsorption, and proximal tubule cell TIMP2/IGFBP7 urinary leakage seem to be the most likely mechanisms.
Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC
Authors: Jonathan W. Riess, David R. Gandara, Garrett M. Frampton, Russell Madison, Nir Peled, Jose A. Bufill, Grace K. Dy, Sai-Hong Ignatius Ou, Philip J. Stephens, John D. McPherson, Primo N. Lara, Rebekah A. Burich, Jeffrey S. Ross, Vincent A. Miller, Siraj M. Ali, Philip C. Mack, Alexa B. Schrock
Journal: Journal of Thoracic Oncology (2018)
Predictores de éxito y opciones de rescate del rendez-vous guiado por ecoencoscopia (RV-USE) para acceso biliar tras canulación fallida por CPRE
Authors: M Cimavilla, M De Benito-Sanz, I Peñas-Herrero, J Garcia-Alonso, ST Law, S Sevilla-Ribota, N Mora, P Gil-Simon, C De La Serna-Higuera, M Pérez-Miranda
Journal: Endoscopy (2017)

La canulación fallida por CPRE es infrecuente pero frustrante. El RV-USE permite superarla, pero también fracasa en el 30% de los intentos.
Lung function trajectories using different reference equations in a birth cohort study up to the age of 20 years
Authors: Christiane Lex, Marvin Reuter, Antje Schuster, Linus Grabenhenrich, Carl-Peter Bauer, Ute Hoffmann, Johannes Forster, Fred Zepp, Ulrich Wahn, Thomas Keil, Susanne Lau, Dirk Schramm
Journal: European Respiratory Journal (2018)

<b>Lung function trajectories using different reference equations in a birth cohort up to the age of 20 years show a drop in FEV</b><sub><b>1</b></sub><b>and FVC of both asthmatic and nonasthmatic subjects at the age of 13 years regardless of which reference equations were used</b>http://ow.ly/hxGJ30ktUYE
Need for additional capacity and improved capability for molecular detection of yellow fever virus in European Expert Laboratories: External Quality Assessment, March 2018
Authors: Cristina Domingo, Heinz Ellerbrok, Marion Koopmans, Andreas Nitsche, Katrin Leitmeyer, Rémi N. Charrel, Chantal B.E.M. Reusken
Journal: Eurosurveillance (2018)

An external quality assessment of yellow fever virus (YFV) molecular detection in European laboratories was organised in rapid response to an increase in human cases in Brazil in 2018 with risk of import to Europe. Detection of YFV was assessed among 32 laboratories in 23/31 European Union (EU) and European Economic Area (EEA) countries and two laboratories in one non-EU/EEA country. Adequate capabilities were lacking in 10/23 countries; five did not participate as they lacked implemented assays.
Carbohydrate requirements are increased
Authors: M. Brudenell
Journal: BMJ (1995)

EDITOR,--D F O'Sullivan found that advice on breast feeding for his diabetic wife was hard to come by.1 This is surprising, since as long ago as 1983 Dodderidge and Wichelow conducted a survey at the diabetic pregnancy unit at King's College Hospital and found that, with good antenatal advice and …
Desarrollo de apósitos de colon con plasma rico en plaquetas (PRP) para prevenir las complicaciones de las escaras tras la terapéutica endoscópica (Beca FSEED 2015)
Authors: V Lorenzo-Zúñiga García, J Boix, V Moreno De Vega, I Marín, N Caballero, I Bon, R Bartolí
Journal: Endoscopy (2017)

Se ha demostrado la eficacia de la aplicación de hidrogeles basados en plasma rico en plaquetas (PRP) (1) o la combinación de sustancias biocompatibles (BiBio) (2), en la prevención de las complicaciones de la resección endoscópica. Se evaluó la utilidad de un apósito basado en PRP y BiBio (PRP+BiBio) para prevenir complicaciones derivadas del daño térmico en modelos animales de rata y cerdo.
Abstract P324: Implications of ACC/AHA Cholesterol Guidelines on Statin Underutilization for Prevention of Cardiovascular Disease in Diabetes Mellitus among Several U.S. Networks of Community Health Centers
Authors: Ehimare Akhabue, Sarah S Rittner, Joseph E Carroll, Philip M Crawford, Lydia Dant, Reesa Laws, Michael C Leo, Jon Puro, Stephen D Persell
Journal: Circulation (2017)

Introduction: Little is known about statin underuse among diabetes (DM) patients cared for in community health centers (CHCs), which tend to serve socioeconomically disadvantaged populations. Implications of the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines on preexisting gaps in statin treatment in this population are unclear. Hypothesis: Substantial statin underutilization will exist regardless of differences between guidelines. Methods: We included 32,440 adults (45% male, 63% non-white, 28% uninsured/Medicaid) with DM aged 40 to 75 years who received care within 16 CHC groups in eleven states in the Community Health Applied Research Network (CHARN) during 2013. Statin prescribing was analyzed as a function of concordance with the National Cholesterol Education Program Adult Treatment Panel (ATPIII) 2001 guideline and ACC/AHA 2013 guideline. Results: More patients were concordant with the ACC/AHA (52.8%) versus ATPIII (36.2%) guideline. Female gender was independently associated with lower concordance for both guidelines [OR 0.90 CI (0.85-0.94) and OR 0.84 CI (0.80-0.88) respectively]. Black race was associated with lower concordance with ATPIII but not ACC/AHA. Being insured, Asian/Pacific Islander or primarily Spanish speaking were associated with greater concordance for both guidelines. 35% (11526/32440) of the cohort were concordant with neither guideline (Figure), the majority (80%) having no statin prescribed. 28% (9168/32440) were concordant with ACC/AHA guidelines but not ATPIII guidelines. 8.5% of these patients had an LDL &gt;160 despite having a medium or high intensity statin prescribed. 12% (3772/32440) were concordant with ATPIII but not ACC/AHA guidelines. Most of these patients had an LDL between 70-99 mg/dl with no or a low intensity statin prescribed. Conclusions: Opportunities exist to improve cholesterol management in DM patients in CHCs. Addressing care gaps could improve cardiovascular disease prevention in this high risk population.
A Longitudinal Investigation of Internalized Stigma, Constrained Disclosure, and Quality of Life Across 12 Weeks in Lung Cancer Patients on Active Oncologic Treatment
Authors: Timothy J. Williamson, Alyssa K. Choi, Julie C. Kim, Edward B. Garon, Jenessa R. Shapiro, Michael R. Irwin, Jonathan W. Goldman, Krikor Bornyazan, James M. Carroll, Annette L. Stanton
Journal: Journal of Thoracic Oncology (2018)
Prevalence of Preoperative Opioid Use and Characteristics Associated With Opioid Use Among Patients Presenting for Surgery
Authors: Paul E. Hilliard, Jennifer Waljee, Stephanie Moser, Lynn Metz, Michael Mathis, Jenna Goesling, David Cron, Daniel J. Clauw, Michael Englesbe, Goncalo Abecasis, Chad M. Brummett
Journal: JAMA Surgery (2018)

Patterns of preoperative opioid use are not well characterized across different surgical services, and studies in this patient population have lacked important self-reported data of pain and affect.To assess the prevalence of preoperative opioid use and the characteristics of these patients in a broadly representative surgical cohort.Cross-sectional, observational study of patients undergoing surgery at a tertiary care academic medical center. Data were collected as a part of large prospective institutional research registries from March 1, 2010, through April 30, 2016.Preoperative patient and procedural characteristics, including prospectively assessed self-reported pain and functional measures.Patient-reported opioid use before surgery.Of the total 34 186 patients recruited (54.2% women; mean [SD] age, 53.1 [16.1] years), preoperative opioid use was reported in 7894 (23.1%). The most common opioids used were hydrocodone bitartrate (4685 [59.4%]), tramadol hydrochloride (1677 [21.2%]), and oxycodone hydrochloride (1442 [18.3%]). Age of 31 to 40 years (adjusted odds ratio [aOR], 1.26; 95% CI, 1.10-1.45), tobacco use (former use aOR, 1.32 [95% CI, 1.22-1.42]; current use aOR, 1.62 [95% CI, 1.48-1.78]), illicit drug use (aOR, 1.74; 95% CI, 1.16-2.60), higher pain severity (aOR, 1.33; 95% CI, 1.31-1.35), depression (aOR, 1.22; 95% CI, 1.12-1.33), higher Fibromyalgia Survey scores (aOR, 1.06, 95% CI, 1.05-1.07), lower life satisfaction (aOR, 0.95, 95% CI, 0.93-0.96), and more medical comorbidities (American Society of Anesthesiology score aOR, 1.47 [95% CI, 1.37-1.58]; Charlson Comorbidity Index aOR, 1.29 [95% CI, 1.18-1.41]) were all independently associated with preoperative opioid use. Preoperative opioid use was most commonly reported by patients undergoing orthopedic (226 [65.1%]) and neurosurgical spinal (596 [55.1%]) procedures and least common among patients undergoing thoracic procedures (244 [15.7%]). After adjusting for patient characteristics, the patients undergoing lower extremity procedures were most likely to report preoperative opioid use (aOR, 3.61; 95% CI, 2.81-4.64), as well as those undergoing pelvic (excluding hip) (aOR, 3.09; 95% CI, 1.88-5.08), upper extremity (aOR, 3.07; 95% CI, 2.12-4.45), and spinal or spinal cord (aOR, 2.68; 95% CI, 2.15-3.32) procedures, with the group undergoing intrathoracic surgery as the reference group.In this large study of preoperative opioid use that includes patient-reported outcome measures, more than 1 in 4 patients presenting for surgery reported opioid use. These data provide important insights into this complicated patient population that would appear to help guide future preoperative optimization and perioperative opioid-weaning interventions.
A fluorescent chemical probe CDy9 selectively stains and enables the isolation of live naïve mouse embryonic stem cells
Authors: Seung-Ju Cho, Keun-Tae Kim, Jong-Soo Kim, Ok-Seon Kwon, Young-Hyun Go, Nam-Young Kang, Haejeong Heo, Mi-Rang Kim, Dong Wook Han, Sung-Hwan Moon, Young-Tae Chang, Hyuk-Jin Cha
Journal: Biomaterials (2018)
A team effort: natural killer cells on the first leg of the tumor immunity relay race
Authors: Timothy B. Fessenden, Ellen Duong, Stefani Spranger
Journal: Journal for ImmunoTherapy of Cancer (2018)

Recent work by Böttcher and colleagues defines a new role for Natural Killer cells in the anti-tumor immune response, arriving early into the tumor microenvironment before passing the baton to DC1 dendritic cells. DC1 dendritic cells subsequently activate CD8+ T cells resulting in effective anti-tumor immunity. This work highlights the cooperative nature of anti-tumor immunity set in motion by Natural Killer cells, and immune evasion by tumors through their exclusion.
This reduction in risk is deemed worth while in other circumstances
Authors: P. Blenkiron
Journal: BMJ (1996)

and vascular invasion is adequately assessed only in resected specimens.For that reason any woman having conservation surgery should be warned that if histological examination of the resected specimen shows adverse factors she will need a mastectomy later.While I accept that there may be no definite evidence at present associating better local control with improved survival, I think that most of us feel uneasy when we see local recurrence in a conserved breast and wonder whether we have jeopardised that patient's chances oflong term survival.Finally, and until we have a cast iron method of detecting occult axillary lymph node metastasis before surgery, a level II or III axillary dissection must be performed in all patients having conservation surgery for invasive carcinoma.
Abstract 15742: Long Term Clinical Outcomes and Major Adverse Cardiac Event Rates of Enhanced External Counterpulsation Therapy in the Real World Settings in Patients with Coronary Artery Disease and Left Ventricular Dysfunction
Authors: Ozlem Soran, Elizabeth D Kennard, Sheryl Kelsey
Journal: Circulation (2011)

Objectives: Enhanced external counterpulsation (EECP) is a noninvasive circulatory assist device that has recently emerged as a treatment option for refractory angina in left ventricular dysfunctio...