tbuckley/cabot-search huggingface dataset:
COMP-18. MACHINE LEARNING DIFFERENTIATION BETWEEN PLEXIFORM NEUROFIBROMAS AND MALIGNANT NERVE SHEATH TUMORS IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) BASED ON MRI
Authors: Dafna Ben Bashat, Moran Artzi, Liat Ben-Sira, Felix Bokstein
Journal: Neuro-Oncology (2018)

Peripheral neurofibromas (NF) represent one of the most common clinical presentations of the NF1. About 10% of patients with NF1 develop malignant peripheral nerve-sheath tumours (MPNST), which is a major cause of morbidity in NF1 patients. Improved prognosis can be achieved if MPNST are diagnosed at an early stage permitting ablative surgery with wide resection margins. Better understanding regarding the natural history and biology of MPNST has been obtained in the last decade, however existing imaging modalities are still imperfect for diagnosis of MPNST. The aim of this study was to use a machine learning method in order to differentiate between benign plexiform neurofibromas from MPNST in patients with NF1 based on conventional MRI methods. Among 23 NF1 patients with pathologically-defined MPNST treated in the last decade in TASMC, seven patients with available preoperative MRI studies were included in the study. For comparison, 7 patients with benign plexiform neurofibromas were chosen from the database of the Gilbert Israeli Neurofibromatosis Center. Regions of interest at tumor areas were extracted from the post contrast 2D T1-weighted spin-echo images acquired on 1.5/3T MRI systems. For each patient, speeded-up-robust (SURF) features were extracted from lesion areas using Matlab bagOfFeatures algorithm. The algorithm was trained with number of visual words =500, grid point selection method, strongest features=0.8 and grid step size (in pixels)=[5 5]. The algorithm was tested with 100 iterations, with the data being randomly split into training (80%) and testing (20%) datasets. A code-book of lesion representations was generated for each group and was given as input to the support-vector-machine (SVM) classifier. Classification results achieved mean accuracy=80%, mean sensitivity=72% and mean specificity=87%. Our preliminary results suggest that a quantitative image representation method based on Bag-of-Features may assist in the classification between benign plexiform neurofibromas and MPNST in NF1.
Liraglutide Reduces Cardiovascular Events and Mortality in Type 2 Diabetes Mellitus Independently of Baseline Low-Density Lipoprotein Cholesterol Levels and Statin Use
Authors: Subodh Verma, Lawrence A. Leiter, C. David Mazer, Stephen C. Bain, John Buse, Steve Marso, Michael Nauck, Bernard Zinman, Heidrun Bosch-Traberg, Søren Rasmussen, Marie M. Michelsen, Deepak L. Bhatt
Journal: Circulation (2018)
Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy
Authors: Steven T. Szabo, Michael J. Thorpy, Geert Mayer, John H. Peever, Thomas S. Kilduff
Journal: Sleep Medicine Reviews (2018)

Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Although only a few drugs have received regulatory approval for narcolepsy to date, treatment involves diverse medications that affect multiple biochemical targets and neural circuits. Clinical trials have demonstrated efficacy for the following classes of drugs as narcolepsy treatments: alerting medications (amphetamine, methylphenidate, modafinil/armodafinil, solriamfetol [JZP-110]), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), sodium oxybate, and the H3-receptor inverse agonist/antagonist pitolisant. Enhanced catecholamine availability and regulation of locus coeruleus (LC) norepinephrine (NE) neuron activity is likely central to the therapeutic activity of most of these compounds. LC NE neurons are integral to sleep/wake regulation and muscle tone; reduced excitatory input to the LC due to compromise of Hcrt/orexin neurons (likely due to autoimmune factors) results in LC NE dysregulation and contributes to narcolepsy/cataplexy symptoms. Agents that increase catecholamines and/or LC activity may mitigate EDS and cataplexy by elevating NE regulation of GABAergic inputs from the amygdala. Consequently, novel medications and treatment strategies aimed at preserving and/or modulating Hcrt/orexin-LC circuit integrity are warranted in narcolepsy/cataplexy.
Abstract 17692: Arrhythmogenic Mechanisms in Hemorrhagic Shock-induced Heart and Comparable Effect of Different Hemoglobin Concentration of Two Artificial Oxygen Carriers
Authors: Bonpei Takase, Yuko Higashimura, Yoshihiro Tanaka, Kenichi Hashmoto
Journal: Circulation (2015)

Lethal ventricular arrhythmias (VT/VF) are serious complications after resuscitation of severe hemorrhagic shock (HS). To investigate mechanisms of arrhythmogenesis after HS and a role of two different concentration of oxygenated liposome-encapsulated human hemoglobin (LHb [Hgb=6g] or HbV [Hgb=10g]), optical mapping analysis (OMP) and electrophysiological study (EPS) were performed using rat HS model. HS was induced by withdrawing 30% blood from aorta (shock alone). Rats were resuscitated by transfusing saline, 5% albumin (5%ALB), LHb, HbV or oxygenated autologous washed red blood cells (wRBC: n=7, per group). After excising heart, OMP and EPS were performed in isolated Langendorff-perfused hearts. OMP revealed abnormal ventricular conduction delay (VCD) with impaired action potential duration dispersion (APDd) in both ventricles in shock alone, saline, and 5%ALB whereas VCD and APDd were substantially attenuated in LHb, HbV or wRBC (a). VT/VF was easily provoked by burst pacing stimulus to LV in saline and 5%ALB while few VT/VF was induced in LHb, LbV or wRBC (b). Conclusion: Ventricular electrical remodeling of abnormal VCD and APDd after HS causes VT/VF. LHb, LbV and wRBC comparably prevent VT/VF possible by attenuating ischemia-reperfusion injury in HS. Especially, even low concentration of hemoglobin in LHb is comparably effective with closely normal concentration of HbV.
Prevalence and Nature of Financial Considerations Documented in Narrative Clinical Records in Intensive Care Units
Authors: Deborah D. Gordon, Ihsaan Patel, Amelia M. Pellegrini, Roy H. Perlis
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The extent to which financial considerations alter intensive care unit (ICU) decision making is poorly understood. <h3>Objectives</h3> To characterize the prevalence and nature of financial considerations documented in narrative clinical records and their association with patient-level demographic and clinical features. <h3>Design, Setting, and Participants</h3> In silico cohort study applying natural language processing to narrative notes from the Medical Information Mart for Intensive Care (MIMIC-III) study. Data from all individuals hospitalized between June 1, 2001, and October 31, 2012, in the ICU of Beth Israel Deaconess Medical Center were analyzed from April 1 to April 30, 2018. <h3>Main Outcomes and Measure</h3> Presence of financial considerations in narrative clinical notes. <h3>Results</h3> Among 46 146 index ICU admissions, 1936 patients (4.2%) were identified with at least 1 note reflecting financial considerations during the ICU stay. Of these 1936 patients, 1135 (58.6%) were male, with a mean (SD) age of 38.8 (28.4) years and mean (SD) length of stay of 21.7 (27.1) days. Among the remaining 44 210 admissions in the cohort, 24 780 (56.1%) were male, with a mean (SD) age of 48.6 (32.1) years and mean (SD) length of stay of 9.2 (11.4) days. Among the 46 146 admissions, 142 (0.3%) included notes describing a change in the discharge plan, 142 (0.3%) describing a change in the treatment plan, and 303 (0.7%) describing a change in medication or previous nonadherence to medication associated with financial considerations. In logistic regression models adjusted for age, sex, marital status, and insurance type, longer hospital stays were significantly associated with the presence of financial notes (odds ratio, 1.01; 95% CI, 1.01-1.01). <h3>Conclusions and Relevance</h3> In this study, among patients in the ICU, clinical notes document the association of financial considerations with care decisions. Although such notes likely underestimate the frequency of such considerations, they highlight the need to develop better systematic approaches to understanding how financial constraints may alter care decisions in US health systems.
THU0568 Biosimilar use in patients with juvenile idiopathic arthritis in a real-world setting in the united kingdom
Authors: D. De Cock, L. Kearsley-Fleet, R. Davies, E. Baildam, M. Beresford, H. Foster, T. Southwood, W. Thomson, K. Hyrich
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Although biosimilars are routinely used in adults with musculoskeletal diseases, there are limited data regarding the use of biosimilars in patients with juvenile idiopathic arthritis(JIA). <h3>Objectives</h3> To describe the characteristics of patients with JIA starting biosimilars in the United Kingdom (UK) following their approval in the UK with musculoskeletal diseases. <h3>Methods</h3> Patients were selected from the Biologics for Children with Rheumatic Diseases (BCRD) study, launched in 2010, an ongoing prospective UK study of biologic therapies other than the etanercept originator (followed in a separate parallel study) in JIA. Baseline information is collected via questionnaires completed by the treating physician or affiliated clinical research nurse. Follow-up data including disease activity measures and changes in drug therapy are collected at 6 months, 1 year and annually thereafter. From 30-Sept-2015, data has been captured on 3 biosimilars available in the UK: 2 infliximab and 1 etanercept biosimilar. <h3>Results</h3> To 12-Dec-2017, 58 patients were identified in the BCRD study starting a biosimilar; 48 (84%) infliximab and 10(17%) etanercept biosimilars (table 1). Of these, 36 (62%) started a biosimilaras their first biologic therapy. Seventeen (29%) switched to a biosimilar from a non-originator biologic. Five patients switched from their originator. Follow-up data ranging from 6 months to 2 years were available in 14 patients. Four patients switched to another biologic in this period, 3 switching from an infliximab biosimilar to tocilizumab, and 1 etanercept biosimilar patient to adalimumab. Two serious adverse events in a 90 day exposure window were reported, both cases of recurrent uveitis in patients on an infliximab biosimilar switching from a non-originator biologic. <h3>Conclusions</h3> Biosimilars in children and young people are used as both first-line and subsequent-line biologic therapy, although currently few UK children have been switched directly from an originator product. Whether a move towards switching all children receiving originator products to biosimilar products, as has been seen in rheumatoid arthritis, will occur is currently unknown but it is imperative that the safety of these treatment decisions are captured in patient registers. <h3>Disclosure of Interest</h3> None declared
CSIG-26. MOLECULAR DETERMINANTS OF SENSITIVITY TO PI3K/AKT/mTOR PATHWAY INHIBITION IN GLIOBLASTOMA
Authors: Caroline von Achenbach, Michael Weller, Kerstin Kaulich, Dorothee Gramatzki, Angela Zacher, Doriano Fabbro, Guido Reifenberger, Emese Szabo
Journal: Neuro-Oncology (2018)

Molecular genetic aberrations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are common in human cancers including glioblastoma, yet, novel therapeutic approaches targeting this pathway in glioblastoma have had limited success to date. Here we analyzed the molecular mechanisms determining sensitivity to PI3K/AKT/mTOR inhibition using gene silencing or pharmacological inhibition by assessing target inhibition, modulation of down-stream signaling pathways, viability, proliferation, and clonogenicity (sphere formation) in human isocitrate dehydrogenase (IDH) wild-type long-term cell (LTC) lines and glioma-initiating cells (GIC). Glioma cells including GIC in particular were universally sensitive to growth inhibition induced by PQR309, a novel, dual pan-PI3K/AKT/mTOR antagonist in vitro. Cells exhibited profound growth arrest, but little apoptotic or necrotic cell death as confirmed by electron microscopy; yet, there was evidence of senescence. Cell lines with high basal levels of phosphorylated (active) AKT, low levels of phosphorylated (inactive) protein translation repressor eukaryotic initiation factor (eIF) 4E-binding protein 1 (p4E-BP1), and high levels of Ser9-phosphorylated (inactive) glycogen synthase kinase 3 beta (pGSK3β) were more sensitive to PQR309. Accordingly, PQR309 acted synergistically in combination with AKT inhibitors to inhibit clonogenicity or spherogenicity in vitro, indicating that persistent AKT activity may represent an escape mechanism from PI3K/AKT/mTOR-targeted therapy. In vivo studies confirmed the anti-glioma activity of PQR309 alone or in combination with AKT inhibition in the orthotopic LN-229 glioma model. Altogether, these data may help to stratify or enrich for patients likely to benefit from PI3K/AKT/mTOR inhibition in future clinical trials of targeted therapy in glioblastoma.
Assessment of Time-Series Machine Learning Methods for Forecasting Hospital Discharge Volume
Authors: Thomas H. McCoy, Amelia M. Pellegrini, Roy H. Perlis
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Forecasting the volume of hospital discharges has important implications for resource allocation and represents an opportunity to improve patient safety at periods of elevated risk. <h3>Objective</h3> To determine the performance of a new time-series machine learning method for forecasting hospital discharge volume compared with simpler methods. <h3>Design</h3> A retrospective cohort study of daily hospital discharge volumes at 2 large, New England academic medical centers between January 1, 2005, and December 31, 2014 (hospital 1), or January 1, 2005, and December 31, 2010 (hospital 2), comparing time-series forecasting methods for prediction was performed. Data analysis was conducted from February 28, 2017, to August 30, 2018. Group-level data for all discharges from inpatient units were included. In addition to conventional methods, a technique originally developed for allocating data center resources, and comparison strategies for incorporating prior data and frequency of model updates, was conducted to identify the model application that optimized forecast accuracy. <h3>Main Outcomes and Measures</h3> Model calibration as measured by<i>R</i><sup>2</sup>and, secondarily, number of days with errors greater than 1 SD of daily volume. <h3>Results</h3> During the forecasted year, hospital 1 had 54 411 discharges (daily mean, 149) and hospital 2 had 47 456 discharges (daily mean, 130). The machine learning method was well calibrated at both sites (<i>R</i><sup>2</sup>, 0.843 and 0.726, respectively) and made errors greater than 1 SD of daily volume on only 13 and 22 days, respectively, of the forecast year at the 2 sites. Last-value-carried-forward models performed somewhat less well (calibration<i>R</i><sup>2</sup>, 0.781 and 0.596, respectively) with 13 and 46 errors of 1 SD or greater, respectively. More frequent retraining and training sets of longer than 1 year had minimal effects on the machine learning method's performance. <h3>Conclusions and Relevance</h3> Volume of hospital discharges can perhaps be reliably forecasted using simple carry-forward models as well as methods drawn from machine learning. The benefit of the latter does not appear to be dependent on extensive training data and may enable forecasts up to 1 year in advance with superior absolute accuracy to carry-forward models.
Ras-induced Interleukin-8 expression plays a critical role in tumor growth and angiogenesis
Authors: Anke Sparmann, Dafna Bar-Sagi
Journal: Cancer Research (2004)

1749   Ras proteins are important regulators of cell proliferation and their constitutive activation is a key event in cancer development. To discover novel effector pathways that might contribute to the oncogenic properties of Ras, we used oligonucleotide-based DNA microarrays to analyze transcriptional changes resulting from constitutive Ras signaling. We performed the expression analyses with HeLa stable cell lines expressing activated RasG12→V transgenes under a tetracycline responsive promoter (Tet-Off™ Expression System). This system not only mediates tight on/off regulation of gene expression; it also permits the titration of protein levels on a single cell basis allowing the study of dose dependent aspects of gene activity. Ras signaling leads to a significant induction of Interleukin-8 (IL-8) mRNA, which is accompanied by a corresponding increase in protein levels. IL-8 is a chemotactic factor for leukocytes and closely associated with the initiation of an acute inflammatory response. Analysis of signal transduction pathways that link Ras to IL-8 up-regulation suggests a direct effect of Ras on the IL-8 promoter, mediated by the synergistic activation of both MAPK-cascades and the PI3K > NFκB pathway. In addition, the Ras-induced accumulation of IL-8 protein is dependent on the activation of p38 MAP-kinase through a post-transcriptional mechanism involving an increase in IL-8 mRNA stability. Investigation of the functional importance of IL-8 in the context of tumorigenesis shows that IL-8 plays a decisive role in RasV12-mediated acceleration of tumor growth in a nude mouse xenograft model. Ablation of IL-8 function is accompanied by a significant reduction in tumor size. This effect is not due to decreased cell proliferation rates, since we observe no change in the mitogenic index of tumors after inhibition of IL-8. However, tumors devoid of functional IL-8 show a marked reduction in vascularization accompanied by vast tissue necrosis. These observations can be correlated with an IL-8-mediated initiation of an early inflammatory reaction in developing neoplasms that triggers tumor vascularization. In addition, IL-8 may act directly to support angiogenesis by promoting endothelial cell proliferation and migration. These results provide a novel mechanism by which tumor cells harboring oncogenic Ras can appropriate inflammatory mediators to recruit immune cells to the tumor site and facilitate neo-angiogenesis, thus setting the stage for subsequent progression to malignancy.
Abstract 15828: Preserved Efficacy of Secretoneurin Gene Therapy in Hypercholesterolemia
Authors: Rudolf Kirchmair, Daniela Lener, Wilfried Schgoer, Karin Albrecht-Schgoer, Ivan Tancevski, Wolfgang-Michael Franz, Peter Marschang, Markus Theurl
Journal: Circulation (2014)

Introduction: Hypercholesterolemia (HC) is a risk factor for the development of cardiovascular disorders and has been identified to be associated with endothelial dysfunction. Like vascular endothe...
NIMG-24. DIFFUSION MRI PRECURSORS TO PROGRESSION IN GRADE II AND III GLIOMA
Authors: Tracy Luks, Yan Li, Marisa Lafontaine, Angela Jakary, Gaurav Inamdar, Michael Wahl, Susan Chang, Sarah Nelson, Javier Villanueva-Meyer
Journal: Neuro-Oncology (2018)

The goal of this project is to identify serial advanced imaging markers that can reveal tumor progression in grade II and III gliomas prior to the to the onset of new contrast enhancement or the expansion of FLAIR abnormality. Nineteen lower grade glioma patients were identified with tumor progression during their participation in research on serial advanced MR imaging and spectroscopy at standard of care timepoints (2–6 months). The average number of scans acquired prior to progression was 7 (range = 12–3). The 3T MRI examination included T1-weighted IRSPGR, T2-weighted FSE, T2 FLAIR, and 6 directional diffusion weighted imaging. Maps of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were calculated, and percentiles (10th, 50th, 90th) from histograms of normalized intensities. Serial images were aligned to the baseline image. Regions of Interest (ROIs) were defined for the entire T2 FLAIR lesion, and when present, the contrast-enhancing (CE) T1 lesion at each timepoint. In addition, we created a Progression ROI consisting of the region that was normal on the baseline T2 FLAIR but abnormal at the time of clinical progression, and a Baseline ROI consisting of the region that was abnormal at baseline and progression. Serial imaging parameters were acquired for each of these ROIs at every timepoint. We determined the imaging parameters with significant changes within the ROIs leading up to the time of progression using repeated-measures analyses of variance. Leading up to the time of progression, there were significant declines in median and 10% normalized ADC and 10% normalized FA within the Baseline T2 FLAIR abnormality ROI. Median normalized ADC also declined significantly in the Progression ROI, indicating changes in diffusion parameters prior to the onset of T2 FLAIR abnormality and the clinical determination of progression.
ANGI-15. PDGF-MEDIATED MESENCHYMAL TRANSFORMATION RENDERS ENDOTHELIAL RESISTANCE TO ANTI-VEGF TREATMENT IN GLIOBLASTOMA
Authors: Wenjuan Ma, Yanqing Gong, Steven Brem, Yi Fan
Journal: Neuro-Oncology (2018)

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. As such, bevacizumab, a humanized anti-VEGF monoclonal antibody, fails to prolong the overall survival time in patients with newly diagnosed glioblastoma (GBM). Here, we show that endothelial mesenchymal transformation induces GBM resistance to anti-VEGF therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). Analyzing human GBM tumor-derived ECs and mouse EC lineage-derived cells in a genetically engineered GBM model, we show that VEGFR-2 expression is markedly reduced in GBM-associated ECs. Transcriptome analysis by RNA-seq shows abrogated VEGFR2 expression in GBM ECs and reveals a robust genetic reprograming with increased mesenchymal gene expression in these ECs. Furthermore, we identify a PDGF/NF-κB/Snail axis that controls mesenchymal transformation and reduces VEGFR2 expression, which induces EC resistance to anti-VEGF treatment. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in the genetic mouse GBM model. Notably, EC-specific knockout of PDGF receptor-β (PDGFR-β) sensitizes tumors to antibody-based VEGF-neutralizing treatment. Taken together, these findings reveal a previously unidentified mechanism for anti-angiogenic treatment resistance, namely, cell plasticity-driven endothelial unresponsiveness to anti-VEGF treatment, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in GBM and possibly other malignant solid tumors.