tbuckley/cabot-search huggingface dataset:
Target-Based Screening against eIF4A1 Reveals the Marine Natural Product Elatol as a Novel Inhibitor of Translation Initiation with <i>In Vivo</i> Antitumor Activity
Authors: Tara L. Peters, Joseph Tillotson, Alison M. Yeomans, Sarah Wilmore, Elizabeth Lemm, Carlos Jiménez-Romero, Luis A. Amador, Lingxiao Li, Amit D. Amin, Praechompoo Pongtornpipat, Christopher J. Zerio, Andrew J. Ambrose, Gillian Paine-Murrieta, Patricia Greninger, Francisco Vega, Cyril H. Benes, Graham Packham, Abimael D. Rodríguez, Eli Chapman, Jonathan H. Schatz
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site mutagenesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors. Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100× relative dosing, leading to significant activity against lymphoma xenografts. Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy. Clin Cancer Res; 24(17); 4256–70. ©2018 AACR.
The occurrence of human papilloma virus (HPV)-related cancers in human immunodeficiency virus (HIV)-infected women compliant with highly active antiretroviral therapy (HAART).
Authors: Ruth B. Hennebery, William R. Robinson
Journal: Journal of Clinical Oncology (2018)

185 Background: HAART has been demonstrated effective at maintaining immunocompetence (as measured in part by CD4 levels) and reducing the occurrence and severity of cervical cancer in HIV-infected women. Conversely, rapid disease progression, poor treatment response and the development of multiple cancers has been associate with suboptimal HIV therapy and low CD4 counts. Methods: 17 HIV-infected women presenting to an inner-city, academic medical center from 1996-2016 were diagnosed with cervical cancer and at least one other HPV-associated cancer. Data recorded include: year of diagnosis and treatment for cervical cancer; the type, year of diagnosis and treatment of subsequent HPV-associated cancers; compliance with HAART and CD4 counts at diagnosis and death (if applicable). Results: 15/17 (88.2%) used HAART and had CD4 counts &gt; 200 at cervical cancer diagnosis. The time from diagnosis of cervical cancer to a second HPV-associated cancer was 0-19 years, with 52.9% developing a second cancer within 3 years. Second cancer diagnoses included vulvar(9), vaginal(2), anal(3), oropharyngeal(1), urethral(1), and bladder/urethral(1). Seven patients developed third cancers: anal(3), oropharyngeal(3), vaginal(1). Conclusions: Despite the effective use of HAART, HIV-infected women appear to be at risk for the development of multiple cancers following a diagnosis of cervical cancer, even years to decades later. Screening for HPV-associated cancers (including oropharyngeal) should therefore be maintained and emphasized, even in highly compliant subjects with adequate CD4 levels.
Predictors of survival after loco-regional therapy (LRT) in stage 4 breast cancer (BC).
Authors: Anuhya Kommalapati, Sri Harsha Tella, Apar Kishor Ganti, Pavankumar Tandra
Journal: Journal of Clinical Oncology (2018)

1083 Background: Recent randomized trials evaluating the role of surgery in de novo stage 4 BC yielded mixed results indicating that patient/tumor characteristics might influence the survival. We analyzed the predictors of survival after LRT in stage 4 BC by using National Cancer Data Base (NCDB). Methods: Retrospective analysis of histologically confirmed infiltrative ductal (IDC), lobular (LC) and metaplastic stage 4 BC patients from 2004-2015 using NCDB. The study cohort was divided into 2 subsets based on the therapy received: no LRT and LRT (surgery ± radiation). The LRT subset was randomized into training and validation cohorts. In the training cohort, Cox proportional method was used to calculate HRs based on which a 17 point survival prediction scoring system was developed (Table). Both the cohorts were stratified into 3 groups based on the scores- group (G)1 (0-3), G2 (4-7) and G3 (8-17). Kaplan Meier (KM) method and log-rank test were used to compare survival among the 3 groups. We validated the prognostic score by comparing the OS between the respective groups in each cohort. Results: A total of 67,978 patients met the inclusion criteria (median age 61 y). The patients in LRT subset (21,120) had significantly better survival (median: 45 vs 24 m) (p < .0001). The 3 groups in training cohort showed significant difference in the OS (p < 0.0001) – G1 having better prognosis. The 3-year OS rates of the groups were 84% (G1), 66% (G2), and 38% (G3). On validation, comparable OS was seen between the respective groups in each cohort (p = 0.77). Conclusions: LRT was associated with improved OS in de novo stage 4 BC. Based on the patient/tumor characteristics, we developed a prediction model to characterize the prognostication in patients undergoing LRT for stage 4 BC. Parameter HR (CI does not include 1);p < 0.05 Score Age - - ≤49 - 0 50-74 1.17 1 ≥75 2.19 2 Race - - White - 0 Black 1.18 1 CDCC - - 0-1 - 0 2-3 1.72 1 Grade - - 1-2 - 0 3-4 1.45 1 Histology - - IDC - 0 LC 1.21 1 Metaplastic 2.06 2 Receptor status - - TP - 0 HR+/HER- 1.60 1 HR-/HER+ 1.46 1 TN 4.54 3 Metastasis - - Bone 1.36 1 Brain 2.48 2 Liver 1.44 1 Lung 1.31 1 All 4.36 3 Combos 2.65 2 T4 1.25 1 No Radiation 1.40 1 Surgical margins positive 1.39 1 Lymphovascular invasion 1.23 1
Meeting requirements for survivorship visits: Interventions for patient identification.
Authors: Nancy K. Termer, Margie Richardson, M Jacob Adams, Alexander Alongi, Patricia Bellohusen, Lauren B. Bruckner, Richard Cowen, Susan Fritsch, Dwight Hettler, Sarah L. Kerns, Chintan Pandya, AnnaLynn Williams, Louis S. Constine
Journal: Journal of Clinical Oncology (2018)

59 Background: A major challenge in providing quality survivorship care to cancer patients is efficiently and effectively identifying and scheduling patients who need a Survivorship Visit (SV). While the Commission on Cancer (CoC) Standard 3.3 defines which patients require a Survivorship Care Plan (SCP), staff need to operationalize the definition and search the clinic’s patient records on a regular basis to accurately identify eligible patients. This is a challenge for a busy cancer center. Methods: In July 2017 the Judy DiMarzo Cancer Survivorship Program instituted a full time Data Analyst (DA) to assist in identifying survivors using the OncoLog Cancer Registry and the Electronic Medical Record (EMR). Previously the identification process was limited to the EMR, and the Survivorship Program Nurse Coordinator (NC) was a combined role overseeing metrics, identifying patients and assisting with SVs. Currently the DA has piloted a method extracting data monthly from OncoLog and the EMR to assess eligibility of Standard 3.3. The data is compiled and sent to the NC who assists the cancer-specific service lines responsible for the patients identified to ensure SVs occur in a timely manner. Results: Our pilot intervention resulted in a 283% increase in SVs per month, from an average of 30 SVs to 115 SVs per month. The overall achievement for the CoC SV delivery requirement increased from 16% prior to the intervention to 33% in just 3 months. GI increased from 5% to 20%. Lung increased from 16% to 39%. The average SV was 3 months after the end of treatment. Approximately 60 hours was dedicated to establishing this method and 35 hours per month in the eligibility, identification process. Conclusions: By adding a DA role, extracting data from Oncolog and the EMR, as well as increasing accountability at the service line level to improve identification and scheduling of eligible patients, the delivery of SCPs to eligible patients substantially increased. Nevertheless this process is time consuming and will likely not be sufficient to ensure that all eligible survivors receive appropriate care. Consequently, additional, systematic improvements in this process should be explored such as EMR methodologies to automate patient identification.
Abstract 11123: Intrinsic and Induced Left Bundle Branch Block are Not Interchangeable
Authors: Daniel R Ludwig, Hidekazu Tanaka, Mati Friehling, John Gorcsan, David Schwartzman
Journal: Circulation (2012)

Background:  An extensive literature attests to the toxic impact of left bundle branch block (LBBB) on left ventricular (LV) mechanical function, whether the LBBB is naturally occurring (intrinsic) or is caused by right ventricular (RV) pacing (induced). In regard to impact on LV mechanical function, a preponderance of the literature would suggest that intrinsic and induced LBBB are equivalent.   Methods and Results:  Twenty-one patients with intrinsic LBBB, intact atrioventricular conduction, and an implanted pacing device with right atrial and ventricular leads were studied. Each patient underwent echocardiographic imaging during two conditions: 1. atrial pacing (intrinsic); 2. atrial and ventricular pacing (AV delay 30 milliseconds; induced). Compared to intrinsic LBBB, induced LBBB was associated with diminished LV ejection fraction (22±7 vs 25±7 %, p   Conclusions:  Intrinsic and induced LBBB are dissimilar. Relative to intrinsic LBBB, RV pacing places a larger mechanical burden on the LV. The use of RV pacing in cardiac resycnhronization therapy should be reconsidered. If RV pacing is to be used, and LV lead location is to be targeted to the region of latest LV mechanical activation, this assay should be performed during induced LBBB and not intrinsic LBBB.
Clinical assessment of acute lateral ankle sprain injuries (ROAST): 2019 consensus statement and recommendations of the International Ankle Consortium
Authors: Eamonn Delahunt, Chris M Bleakley, Daniela S Bossard, Brian M Caulfield, Carrie L Docherty, Cailbhe Doherty, François Fourchet, Daniel T Fong, Jay Hertel, Claire E Hiller, Thomas W Kaminski, Patrick O McKeon, Kathryn M Refshauge, Alexandria Remus, Evert Verhagen, Bill T Vicenzino, Erik A Wikstrom, Phillip A Gribble
Journal: British Journal of Sports Medicine (2018)

Lateral ankle sprain injury is the most common musculoskeletal injury incurred by individuals who participate in sports and recreational physical activities. Following initial injury, a high proportion of individuals develop long-term injury-associated symptoms and chronic ankle instability. The development of chronic ankle instability is consequent on the interaction of mechanical and sensorimotor insufficiencies/impairments that manifest following acute lateral ankle sprain injury. To reduce the propensity for developing chronic ankle instability, clinical assessments should evaluate whether patients in the acute phase following lateral ankle sprain injury exhibit any mechanical and/or sensorimotor impairments. This modified Delphi study was undertaken under the auspices of the executive committee of the International Ankle Consortium. The primary aim was to develop recommendations, based on expert (n=14) consensus, for structured clinical assessment of acute lateral ankle sprain injuries. After two modified Delphi rounds, consensus was achieved on the clinical assessment of acute lateral ankle sprain injuries. Consensus was reached on a minimum standard clinical diagnostic assessment. Key components of this clinical diagnostic assessment include: establishing the mechanism of injury, as well as the assessment of ankle joint bones and ligaments. Through consensus, the expert panel also developed the International Ankle Consortium Rehabilitation-Oriented ASsessmenT (ROAST). The International Ankle Consortium ROAST will help clinicians identify mechanical and/or sensorimotor impairments that are associated with chronic ankle instability. This consensus statement from the International Ankle Consortium aims to be a key resource for clinicians who regularly assess individuals with acute lateral ankle sprain injuries.
Annals Graphic Medicine - Finding the Funny: Chemotherapy
Authors: Jade R. Blue
Journal: Annals of Internal Medicine (2018)

Web Exclusives5 June 2018Annals Graphic Medicine - Finding the Funny: ChemotherapyFREEJade R. Blue, BA(Hons)Jade R. Blue, BA(Hons)From Ceredigion, Wales, United Kingdom. (J.R.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G17-0018 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Laugh, cry, and reflect with your learners at the messages in this series of cartoons by a patient who reflects on her experiences with chemotherapy for breast cancer. Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Ceredigion, Wales, United Kingdom. (J.R.B.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G17-0018.Author/Illustrator Information: Jade Blue is an English-language teacher and trainer based in the United Kingdom, Germany, and Japan. She also works as a research consultant and editor for Cambridge University Press and writes a reflective blog (http://jadeblueefl.wordpress.com). Her research interests focus on drawing in the classroom and learner autonomy. Jade is passionate about doodling and drawing comics and writes a blog about her work (http://jadesdoodles.wordpress.com).Author Contributions: Conception and design: J.R. Blue.Drafting of the article: J.R. Blue.Final approval of the article: J.R. Blue.Administrative, technical, or logistic support: J.R. Blue. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 5 June 2018Volume 168, Issue 11Page: W24-W30KeywordsBreast cancerCancer chemotherapyChemotherapyConflicts of interestDisclosure ePublished: 5 June 2018 Issue Published: 5 June 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Isle of Wight trust remains in special measures amid significant safety concerns
Authors: Jacqui Wise
Journal: BMJ (2018)

The Isle of Wight NHS Trust will remain in special measures after the healthcare regulator found that significant problems persist about patient safety, nearly two years after concerns were first raised.1

The Care Quality Commission (CQC) said that, despite some improvements since the trust was first placed in special measures in November 2016, further significant improvements to the quality of its services were needed. In January 2018, inspectors examined all core services at the trust and rated it inadequate overall, also rating it inadequate in safety and …
STARD13-correlated ceRNA network-directed inhibition on YAP/TAZ activity suppresses stemness of breast cancer via co-regulating Hippo and Rho-GTPase/F-actin signaling
Authors: Lufeng Zheng, Chenxi Xiang, Xiaoman Li, Qianqian Guo, Lanlan Gao, Haiwei Ni, Yufeng Xia, Tao Xi
Journal: Journal of Hematology & Oncology (2018)

Targeting cancer stem cells is critical for suppressing cancer progression and recurrence. Finding novel markers or related pathways could help eradicate or diagnose cancer in clinic. By constructing STARD13-correlated ceRNA 3′UTR stable overexpression or knockdown breast cancer cells, we aimed to explore the effects of STARD13-correlated ceRNA network on breast cancer stemness in vitro and in vivo. Further RNA-sequencing was used to analyze transcriptome change in combination with functional studies on candidate signaling. Clinical samples obtained from The Cancer Genome Atlas data were used to validate the correlation between STARD13 and related pathways. Finally, in vitro and in vivo experiments were used to examine the effects of STARD13-correlated ceRNA network on chemotherapy sensitivity/resistance. Here, we revealed that this ceRNA network inhibited stemness of breast cancer. Mechanistically, we found that activation of STARD13-correlated ceRNA network was negatively correlated with YAP/TAZ activity in breast cancer. Specifically, this ceRNA network attenuated YAP/TAZ nuclear accumulation and transcriptional activity via collectively modulating Hippo and Rho-GTPase/F-actin signaling. Finally, we demonstrated that YAP/TAZ transcriptional activity regulated by this ceRNA network was involved in chemoresistance. Our results uncover a novel mechanism of YAP/TAZ activation in breast cancer and propose the possibility to drive STARD13-correlated ceRNA network to inhibit breast cancer stem cell traits.
Effects of Repetitive Transendocardial CD34 <sup>+</sup> Cell Transplantation in Patients With Nonischemic Dilated Cardiomyopathy
Authors: Bojan Vrtovec, Gregor Poglajen, Matjaz Sever, Gregor Zemljic, Sabina Frljak, Andraz Cerar, Marko Cukjati, Martina Jaklic, Peter Cernelc, François Haddad, Joseph C. Wu
Journal: Circulation Research (2018)

Preclinical data in heart failure models suggest that repetitive stem cell therapy may be superior to single-dose cell administration.We investigated whether repetitive administration of CD34+ cells is superior to single-dose administration in patients with nonischemic dilated cardiomyopathy.Of 66 patients with dilated cardiomyopathy, New York Heart Association functional class III, and left ventricular ejection fraction (LVEF) <40% enrolled in the study, 60 were randomly allocated to repetitive cell therapy (group A, n=30) or single-cell therapy (group B, n=30). Patients received G-CSF (granulocyte colony-stimulating factor) for 5 days, and 80 million CD34+ cells were collected by apheresis and injected transendocardially. In group A, cell therapy was repeated at 6 months. All patients were followed for 1 year, and the primary end point was the difference in change in LVEF between the groups. At baseline, the groups did not differ in age, sex, LVEF, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or 6-minute walk test distance. When directly comparing groups A and B at 1 year, there was no significant difference in change in LVEF (from 32.2±9.3% to 41.2±6.5% in group A and from 30.0±7.0% to 37.9±5.3% in group B, P=0.40). From baseline to 6 months, both groups improved in LVEF (+6.9±3.3% in group A, P=0.001 and +7.1±3.5% in group B, P=0.001), NT-proBNP (-578±211 pg/mL, P=0.02 and -633±305 pg/mL, P=0.01), and 6-minute walk test (+87±21 m, P=0.03 and +92±25 m, P=0.02). In contrast, we observed no significant changes between 6 months and 1 year (LVEF: +2.1±2.3% in group A, P=0.19 and +0.8±3.1% in group B, P=0.56; NT-proBNP: -215±125 pg/mL, P=0.26 and -33±205 pg/mL, P=0.77; 6-minute walk test: +27±11 m, P=0.2 and +12±18 m, P=0.42).In patients with dilated cardiomyopathy, repetitive CD34+ cell administration does not seem to be associated with superior improvements in LVEF, NT-proBNP, or 6-minute walk test when compared with single-dose cell therapy.URL: http://www.clinicaltrials.gov. Unique identifier: NCT02248532.
Publisher Correction: Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans
Authors: Thomas Gstrein, Andrew Edwards, Anna Přistoupilová, Ines Leca, Martin Breuss, Sandra Pilat-Carotta, Andi H. Hansen, Ratna Tripathy, Anna K. Traunbauer, Tobias Hochstoeger, Gavril Rosoklija, Marco Repic, Lukas Landler, Viktor Stránecký, Gerhard Dürnberger, Thomas M. Keane, Johannes Zuber, David J. Adams, Jonathan Flint, Tomas Honzik, Marta Gut, Sergi Beltran, Karl Mechtler, Elliott Sherr, Stanislav Kmoch, Ivo Gut, David A. Keays
Journal: Nature Neuroscience (2018)
Increasing adherence to adjuvant hormone therapy among breast cancer patients: A smart phone app-based pilot study.
Authors: Jessica L. Krok-Schoen, Michelle Joy Naughton, Gregory S. Young, Jennifer Moon, Electra D. Paskett, Douglas M. Post
Journal: Journal of Clinical Oncology (2018)

e12523 Background: Despite the proven clinical efficacy of adjuvant hormone therapy (AHT) for breast cancer survivors, evidence suggests that up to 50% of patients do not complete treatment as recommended. One strategy to improve non-adherence to AHT is the use of technology-based interventions. Methods: This pilot study examined the feasibility of a smart phone, text-based reminder system to increase adherence and decrease discontinuation of AHT among post-menopausal women with breast cancer. The 3-month intervention consisted of daily text message reminders to take medication, coupled with a dynamic (e.g., feedback on progress) tailored intervention using weekly interactive surveys delivered by a smartphone app. Five clinic sites within the Alliance for Clinical Trials in Oncology participated. Hormone levels were measured prior to AHT initiation and at study exit. Results: Out of the 39 patients recruited to the pilot study, 27 (69.2%) completed all study requirements (completed both the baseline and exit surveys, both blood draws and missed no more than two weekly surveys). Significant improvements were observed pre- to post-intervention for self-reported medication adherence (p = 0.02), mental health (p = 0.007), and perceived stress (p = 0.04). Significant decreases in estradiol, estrogen, and estrone hormone levels were observed from baseline to study exit (p values < 0.001), indicating the accuracy of self-reported AHT adherence. Patients (91.9%) and physicians (100%) agreed that patient participation in the intervention was beneficial. Conclusions: The results of this pilot study were encouraging as it supported patient AHT adherence and improved health-related quality of life. Larger, randomized controlled, longer-term studies are needed to establish the efficacy of the app-based intervention in improving AHT adherence among women receiving treatment for breast cancer. Support: UG1CA189823; ClinicalTrials.gov Identifier: NCT02400060