tbuckley/cabot-search huggingface dataset:
EPEN-08. PHARMACOGENOMICS REVEALS ERBB2 AS A THERAPEUTIC TARGET IN PRIMARY EPENDYMOMA CULTURES
Authors: David Pauck, Sevgi Sarikaya-Seiwert, Viktoria Marquardt, Eunice Paisana, Daniel Picard, Jasmin Bartl, Lena Blümel, Mara Maue, Christian Dimitriadis, Kübra Taban, Ute Fischer, Hans Jakob Steiger, Cláudia Faria, Guido Reifenberger, Arndt Borkhardt, Thomas Beez, Marc Remke
Journal: Neuro-Oncology (2019)

Ependymoma represents the third most common brain tumor entity of childhood. Successful targeted treatment approaches especially for RELA fusion-positive supratentorial ependymomas and posterior fossa type A ependymomas, the two subgroups known to be associated with worst prognosis, have so far not been discovered. We set up a high-throughput drug screening (HTS) pipeline to evaluate therapeutic efficacy of established chemotherapeutic agents and novel anti-cancer compounds currently in phase III and IV studies (n=196) in primary ependymoma cultures (n=12). Assay miniaturization to 1536-well microplates emerged as a key feature to enable drug screening from smallest sample amounts. Primary cultures faithfully recapitulated DNA methylation changes and copy number profiles detected in the corresponding primary tumors. In addition, entity and subgroup affiliation were consistent using molecular neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature, 2018). These results confirm that the (epi)genetic landscape is maintained in short-term primary ependymoma cultures. We revealed remarkable chemoresistance by comparing HTS data of ependymomas to other established pediatric brain tumor models (n=48) and normal tissue controls (n=3). Notably, we identified Neratinib, an irreversible ERBB2 inhibitor, as the most prominent candidate drug amongst multiple targeted therapeutics with its preferential antitumoral activity in a subset of ependymoma cases (n=5). To unravel the mechanism of action of Neratinib, RNA sequencing of treated and untreated ependymoma cell lines (n=3) was conducted demonstrating highly specific abrogation of ERBB2 signaling. In summary, our study demonstrates the feasibility of primary culture drug screening for pediatric brain tumors to identify novel therapeutic approaches. Specifically, we identified preferential antitumoral activity of Neratinib in ependymomas providing a novel therapeutic approach for a largely chemoresistant entity.
Trends in the Use of Common Words and Patient-Centric Language in the Titles of Medical Journals, 1976-2015
Authors: Gregory M. Chen, Sarshan R. Pather, Horace M. DeLisser
Journal: JAMA Network Open (2019)

The language of medical research appears to be intrinsically tied to the culture of medical research and provides a unique window into broader trends in the culture of medicine.
Abstract 18260: Cyclic GMP Enhancing Therapy Promotes Titin Phosphorylation and Corrects High Cardiomyocyte Passive Stiffness in Diastolic Heart Failure
Authors: Nazha Hamdani, Bishu G Kalkidan, Jolanda van der Velden, Ger J Stienen, Margaret M Redfield, Wolfgang A Linke
Journal: Circulation (2012)

Myofiber passive stiffness is lowered by phosphorylation of the giant sarcomeric protein titin, with beneficial effects on diastolic function. Titin can be phosphorylated by cGMP-activated protein kinase (PK)G, a pathway stimulated by B-type natriuretic peptide (BNP) or PDE-5A inhibitor (sildenafil). Whether titin phosphorylation and stiffness are affected by PKG activation in vivo had not been studied. Here we examined how dogs with experimental hypertension and diastolic dysfunction, induced by renal wrapping, respond to treatment with β-blockers, sildenafil, and BNP, in terms of altered titin phosphorylation and passive stiffness. Isolated permeabilized cardiomyocytes from left ventricular (LV) biopsies untreated (n=5), treated with β-blockers (n=7), followed by sildenafil (n=7) and BNP (n=7) were attached to a force transducer and the passive length tension relation (F pas ) was measured between 1.8 and 2.4µm sarcomere length (SL) before and after PKA and PKG administration. We also assessed phosphorylation of myofilament proteins including titin, cMyBPC, desmin, cTnT, cTnI and MLC2 by gel electrophoresis (SYPRO Ruby and ProQ Diamond stain) and expression of titin PEVK, phospho-PEVK, cTnI, phospho-cTnI (at Ser 23/24), PKCα and phospho-PKCα by Western blotting. Compared to untreated cardiomyocytes, F pas was unaltered with β-blocker therapy, but significantly reduced with sildenafil; with BNP F pas did not change further. Ex-vivo administration of PKG lowered F pas of untreated and β-blocker cardiomyocytes to the levels measured in sildenafil and BNP samples, and additional administration of PKA did not further change F pas . Total titin phosphorylation was low in untreated samples and with β-blockade, but significantly increased with sildenafil and BNP. Total cTnI phosphorylation and phospho-cTnI at Ser 23/24 were low in untreated compared to treated samples but were similar between β-blocker, sildenafil and BNP groups. Phospho-PEVK and phospho-PKCα were high in untreated samples and with β-blockade, but reduced with sildenafil and BNP. Acute cGMP enhancing therapy with sildenafil and BNP improves LV diastolic function through correction of a titin phosphorylation deficit, thereby reducing cardiomyocyte passive stiffness.
Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis
Authors: Mohamed Elgendy, Marco Cirò, Amir Hosseini, Jakob Weiszmann, Luca Mazzarella, Elisa Ferrari, Riccardo Cazzoli, Giuseppe Curigliano, Andrea DeCensi, Bernardo Bonanni, Alfredo Budillon, Pier Giuseppe Pelicci, Veerle Janssens, Manfred Ogris, Manuela Baccarini, Luisa Lanfrancone, Wolfram Weckwerth, Marco Foiani, Saverio Minucci
Journal: Cancer Cell (2019)
Erythrapheresis Improves Blood Viscosity Compared to Manuel Procedure in Sickle Cell Disease
Authors: Ait Abdallah Nassim, Connes Philippe, Di Liberto Gaetana, Offredo Lucile, Ranque Brigitte, Debbache Karima, Jebali Amna, Habibi Anoosha, Pirenne France, Galacteros Frédéric, Bartolucci Pablo
Journal: Blood (2016)
Detection of Pediatric Upper Extremity Motor Activity and Deficits With Accelerometry
Authors: Catherine R. Hoyt, Andrew N. Van, Mario Ortega, Jonathan M. Koller, Elyse A. Everett, Annie L. Nguyen, Catherine E. Lang, Bradley L. Schlaggar, Nico U. F. Dosenbach
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Affordable, quantitative methods to screen children for developmental delays are needed. Motor milestones can be an indicator of developmental delay and may be used to track developmental progress. Accelerometry offers a way to gather real-world information about pediatric motor behavior. <h3>Objective</h3> To develop a referent cohort of pediatric accelerometry from bilateral upper extremities (UEs) and determine whether movement can accurately distinguish those with and without motor deficits. <h3>Design, Setting, and Participants</h3> Children aged 0 to 17 years participated in a prospective cohort from December 8, 2014, to December 29, 2017. Children were recruited from Ranken Jordan Pediatric Bridge Hospital, Maryland Heights, Missouri, and Washington University School of Medicine in St Louis, St Louis, Missouri. Typically developing children were included as a referent cohort if they had no history of motor or neurological deficit; consecutive sampling and matching ensured equal representation of sex and age. Children with diagnosed asymmetric motor deficits were included in the motor impaired cohort. <h3>Exposures</h3> Bilateral UE motor activity was measured using wrist-worn accelerometers for a total of 100 hours in 25-hour increments. <h3>Main Outcomes and Measures</h3> To characterize bilateral UE motor activity in a referent cohort for the purpose of detecting irregularities in the future, total activity and the use ratio between UEs were used to describe typically developing children. Asymmetric impairment was classified using the mono-arm use index (MAUI) and bilateral-arm use index (BAUI) to quantify the acceleration of unilateral movements. <h3>Results</h3> A total of 216 children enrolled, and 185 children were included in analysis. Of these, 156 were typically developing, with mean (SD) age 9.1 (5.1) years and 81 boys (52.0%). There were 29 children in the motor impaired cohort, with mean (SD) age 7.4 (4.4) years and 16 boys (55.2%). The combined MAUI and BAUI (mean [SD], 0.86 [0.005] and use ratio (mean [SD], 0.90 [0.008]) had similar F1 values. The area under the curve was also similar between the combined MAUI and BAUI (mean [SD], 0.98 [0.004]) and the use ratio (mean [SD], 0.98 [0.004]). <h3>Conclusions and Relevance</h3> Bilateral UE movement as measured with accelerometry may provide a meaningful metric of real-world motor behavior across childhood. Screening in early childhood remains a challenge; MAUI may provide an effective method for clinicians to measure and visualize real-world motor behavior in children at risk for asymmetrical deficits.
P2.03-043 A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naïve EGFR-Mutated Metastatic Non-Small Cell Lung Cancer
Authors: S. Padda, K. Reckamp, M. Koczywas, J. Neal, J. Kawashima, S. Kong, Y. Xin, D. Huang, H. Wakelee
Journal: Journal of Thoracic Oncology (2017)
Comparison of RECIST, iRECIST, and PERCIST for the Evaluation of Response to PD-1/PD-L1 Blockade Therapy in Patients With Non–Small Cell Lung Cancer
Authors: Lucian Beer, Maximilian Hochmair, Alexander R. Haug, Bernhard Schwabel, Daria Kifjak, Wolfgang Wadsak, Thorsten Fuereder, Hannah Fabikan, Andreas Fazekas, Sophia Schwab, Marius E. Mayerhoefer, Christian Herold, Helmut Prosch
Journal: Clinical Nuclear Medicine (2019)

The aim of this study was to compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the immune RECIST (iRECIST) criteria, and the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 in patients with advanced non-small cell lung cancer treated with programmed cell death protein 1 (PD-1)/programmed cell death protein 1 ligand (PD-L1) inhibitors.This prospective study of 42 patients treated with a PD-1/PD-L1 inhibitor was approved by our institutional review board, and all patients gave written, informed consent. Tumor burden dynamics were assessed on F-FDG PET/CT before and after treatment initiation. Immunotherapeutic responses were evaluated according to RECIST 1.1, iRECIST, and PERCIST 1.0 for the dichotomous groups, responders versus nonresponders. Cohen κ and Wilcoxon signed rank tests were used to evaluate concordance among these criteria. We assessed progression-free survival and overall survival using the Kaplan-Meier estimator.The RECIST 1.1 and PERCIST 1.0 response classifications were discordant in 6 patients (14.2%; κ = 0.581). RECIST 1.1 and iRECIST were discordant in 2 patients, who evidenced pseudoprogression after treatment initiation. Median progression-free survival, as well as overall survival, was significantly longer for responders compared with nonresponders for all criteria (P < 0.001), with no significant difference between the 3 criteria (P > 0.05).RECIST 1.1 and PERCIST 1.0 show only moderate agreement, but both can predict treatment response to PD-1/PD-L1 inhibitor therapy. In case of pseudoprogression, metabolic tumor activity may help to correctly classify treatment response.
Lysed Erythrocyte Membranes Promote Vascular Calcification
Authors: Dimitrios N. Tziakas, Georgios Chalikias, Maria Pavlaki, Dimitra Kareli, Rajinikanth Gogiraju, Astrid Hubert, Elsa Böhm, Petros Stamoulis, Ioannis Drosos, Petros Kikas, Dimitrios Mikroulis, Alexandra Giatromanolaki, George S. Georgiadis, Fotios Konstantinou, Christos Argyriou, Thomas Münzel, Stavros V. Konstantinides, Katrin Schäfer
Journal: Circulation (2019)

Intraplaque hemorrhage promotes atherosclerosis progression, and erythrocytes may contribute to this process. In this study we examined the effects of red blood cells on smooth muscle cell mineralization and vascular calcification and the possible mechanisms involved.Erythrocytes were isolated from human and murine whole blood. Intact and lysed erythrocytes and their membrane fraction or specific erythrocyte components were examined in vitro using diverse calcification assays, ex vivo by using the murine aortic ring calcification model, and in vivo after murine erythrocyte membrane injection into neointimal lesions of hypercholesterolemic apolipoprotein E-deficient mice. Vascular tissues (aortic valves, atherosclerotic carotid artery specimens, abdominal aortic aneurysms) were obtained from patients undergoing surgery.The membrane fraction of lysed, but not intact human erythrocytes promoted mineralization of human arterial smooth muscle cells in culture, as shown by Alizarin red and van Kossa stain and increased alkaline phosphatase activity, and by increased expression of osteoblast-specific transcription factors (eg, runt-related transcription factor 2, osterix) and differentiation markers (eg, osteopontin, osteocalcin, and osterix). Erythrocyte membranes dose-dependently enhanced calcification in murine aortic rings, and extravasated CD235a-positive erythrocytes or Perl iron-positive signals colocalized with calcified areas or osteoblast-like cells in human vascular lesions. Mechanistically, the osteoinductive activity of lysed erythrocytes was localized to their membrane fraction, did not involve membrane lipids, heme, or iron, and was enhanced after removal of the nitric oxide (NO) scavenger hemoglobin. Lysed erythrocyte membranes enhanced calcification to a similar extent as the NO donor diethylenetriamine-NO, and their osteoinductive effects could be further augmented by arginase-1 inhibition (indirectly increasing NO bioavailability). However, the osteoinductive effects of erythrocyte membranes were reduced in human arterial smooth muscle cells treated with the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide or following inhibition of NO synthase or the NO receptor soluble guanylate cyclase. Erythrocytes isolated from endothelial NO synthase-deficient mice exhibited a reduced potency to promote calcification in the aortic ring assay and after injection into murine vascular lesions.Our findings in cells, genetically modified mice, and human vascular specimens suggest that intraplaque hemorrhage with erythrocyte extravasation and lysis promotes osteoblastic differentiation of smooth muscle cells and vascular lesion calcification, and also support a role for erythrocyte-derived NO.
Reverse Erythroblastosis Virus α Antagonism Promotes Homocysteine Catabolism and Ammonia Clearance
Authors: Tianpeng Zhang, Min Chen, Lianxia Guo, Fangjun Yu, Cui Zhou, Haiman Xu, Baojian Wu
Journal: Hepatology (2019)

Metabolic homeostasis of amino acids is essential for human health. Here, we aimed to investigate a potential role for the clock component reverse erythroblastosis virus α (Rev‐erbα) in circadian regulation of amino acid metabolism. RNA‐seq with Rev‐erbα‐/‐ mice showed expression changes in genes involved in amino acid metabolism, particularly, the urea cycle and methionine metabolism. Rev‐erbα ablation increased hepatic mRNA, protein, and enzymatic activity of betaine homocysteine methyltransferase (Bhmt), cystathionine β‐synthase (Cbs), and cystathionine γ‐lyase (Cth) and decreased the levels of plasma and liver homocysteine in mice. Cell‐based assays confirmed negative regulation of these three genes by Rev‐erbα. Combined luciferase reporter, mobility‐shift, and chromatin immunoprecipitation assays identified Rev‐erbα as a transcriptional repressor of Bhmt , Cbs , and Cth . Rev‐erbα ablation or antagonism alleviated chemical‐induced hyperhomocysteinemia in mice. This was accompanied by elevated expressions of Bhmt, Cbs, and Cth. Moreover, Rev‐erbα ablation or antagonism promoted urea production and ammonia clearance. Of urea cycle–related genes, arginase 1 (Arg1), ornithine transcarbamylase (Otc), and carbamoyl‐phosphate synthase 1 (Cps1) expressions were up‐regulated in Rev‐erbα‐/‐ mice. Negative regulation of these urea cycle genes by Rev‐erbα was validated using cell‐based experiments. Mechanistic studies revealed that Rev‐erbα inhibited CCAAT‐enhancer‐binding protein α transactivation to repress the transcription of Arg1 , Cps1 , and Otc . Conclusion: Rev‐erbα antagonism alleviates hyperhomocysteinemia and promotes ammonia clearance. Targeting Rev‐erbα represents an approach for the management of homocysteine‐ and ammonia‐related diseases.
The Cancer Editome Atlas: A Resource for Exploratory Analysis of the Adenosine-to-Inosine RNA Editome in Cancer
Authors: Chui-Hsien Lin, Sean Chun-Chang Chen
Journal: Cancer Research (2019)

Increasing evidence has suggested a role for adenosine-to-inosine RNA editing in carcinogenesis. However, the clinical utility of RNA editing remains limited because functions of the vast majority of editing events remain largely unexplored. To help the cancer research community investigate functional consequences of individual editing events, we have developed a user-friendly bioinformatic resource, The Cancer Editome Atlas (TCEA; http://tcea.tmu.edu.tw). TCEA characterizes >192 million editing events at >4.6 million editing sites from approximately 11,000 samples across 33 cancer types in The Cancer Genome Atlas. Clinical information, miRNA expression, and alteration in miRNA targeting modulated through RNA editing are also integrated into TCEA. TCEA supports several modules to search, analyze, and visualize the cancer editome, providing a solid basis for investigating the oncogenic mechanisms of RNA editing and expediting the identification of therapeutic targets in cancer. SIGNIFICANCE: This user-friendly bioinformatic resource reduces the barrier to analyzing the huge and complex cancer RNA editome that cancer researchers face and facilitates the identification of novel therapeutic targets in cancer.
GENE-12. ANAPLASTIC NEUROEPITHELIAL TUMOR WITH CONDENSED NUCLEI (ANTCON): A NOVEL BRAIN TUMOR ENTITY WITH RECURRENT NTRK FUSION
Authors: David Jones, Britta Ismer, Daniel Schrimpf, David Reuss, Damien Stichel, Belen Casalini, Jens Schittenhelm, Stephan Frank, Henning Boldt, Bjarne Winther-Kristensen, Astrid Marie Sehested, David Scheie, Andrey Korshunov, Jonas Ecker, Till Milde, Kristian Pajtler, Christel Herold-Mende, Olaf Witt, Wolfgang Wick, Stefan M Pfister, Andreas von Deimling, Felix Sahm
Journal: Neuro-Oncology (2019)

Brain tumors presenting with histological and molecular features not matching any established category in the WHO classification are challenging for diagnosticians and clinicians. Albeit rare, these cases can belong to distinct, as of yet not recognized entities. Based on unsupervised clustering of DNA methylation data from >30,000 tumors, we identified a group of tumors forming a cluster separate from all established entities. Histological reports revealed varying diagnoses and WHO grading. DNA and/or RNA sequencing of nine cases revealed NTRK fusions in five samples and fusions involving EGFR, FGFR1 and MET in single cases. Homozygous deletion at 9p21 encompassing CDKN2A/B were detected in 4/9 patients (44%). No other recurrent, focal copy number aberrations were observed. Considering cellular differentiation, histological features of anaplasia with high proliferative activity and the endothelial proliferation, the tumor entity was termed anaplastic neuroepithelial tumor with condensed nuclei (ANTCoN). The clinical findings provisionally support its classification as WHO grade III. The high frequency of NTRK fusions opens opportunities for targeted therapy. As a pre-clinical platform, a representative mouse model of an NTRK2-fused tumor with deletion of CDKN2A/B was generated using in utero electroporation in CD1 immunocompetent mice. A combination of the fusion plus loss-of-function of either p53 or cdkn2a resulted in tumors with a penetrance of 96% and mean latencies of 42.6 and 74.5 days, respectively. Histology of the murine tumors resembled human ANTCoN. This model will allow comparing the efficacy of Trk inhibitors in vivo to accelerate pre-clinical testing towards drug approval. In summary, the identification of this novel entity underlines the concept of the current WHO classification for brain tumors, that virtually all cases can be clearly categorized based on combined histological and molecular profiling. The detection of promising therapeutic targets in such groups, as in ANTCoN, can also provide significant opportunities for treatment.
A Multi-institutional International Analysis of Textbook Outcomes Among Patients Undergoing Curative-Intent Resection of Intrahepatic Cholangiocarcinoma
Authors: Katiuscha Merath, Qinyu Chen, Fabio Bagante, Sorin Alexandrescu, Hugo P. Marques, Luca Aldrighetti, Shishir K. Maithel, Carlo Pulitano, Matthew J. Weiss, Todd W. Bauer, Feng Shen, George A. Poultsides, Olivier Soubrane, Guillaume Martel, B. Groot Koerkamp, Alfredo Guglielmi, Endo Itaru, Jordan M. Cloyd, Timothy M. Pawlik
Journal: JAMA Surgery (2019)

Composite measures may be superior to individual measures for the analysis of hospital performance and quality of surgical care.To determine the incidence of a so-called textbook outcome, a composite measure of the quality of surgical care, among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.This cohort study involved an analysis of a multinational, multi-institutional cohort of patient from 15 major hepatobiliary centers in North America, Europe, Australia, and Asia who underwent curative-intent resection of intrahepatic cholangiocarcinoma between 1993 and 2015. Data analysis was conducted from April 2018 to May 2018.Hospital variation in the composite end point of textbook outcome, defined as negative margins, no perioperative transfusion, no postoperative surgical complications, no prolonged length of stay, no 30-day readmissions, and no 30-day mortality. Secondary end points were factors associated with achieving textbook outcomes.Among 687 patients (of whom 370 [53.9%] were men; median patient age, 61 [range, 18-86] years) undergoing curative-intent resection of intrahepatic cholangiocarcinoma, a textbook outcome was achieved in 175 patients (25.5%). Being 60 years or younger (odds ratio [OR], 1.61 [95% CI, 1.04-2.49]; P = .03), absence of preoperative jaundice (OR, 4.40 [95% CI, 1.28-15.15]; P = .02), no neoadjuvant chemotherapy (OR, 2.57 [95% CI, 1.05-6.29]; P = .04), T1a/T1b-stage disease (OR, 1.58 [95% CI, 1.01-2.49]; P = .049), N0 status (OR, 3.89 [95% CI, 1.77-8.54]; P = .001), and no bile duct resection (OR, 2.46 [95% CI, 1.25-4.84]; P = .009) were independently associated with achieving a textbook outcome after resection. A prolonged length of stay had the greatest negative association with a textbook outcome. A nomogram to assess the probability of textbook outcome was developed and had good accuracy in both the training data set (area under the curve, 0.755) and validation data set (area under the curve, 0.763).In this study, while hepatic resection for intrahepatic cholangiocarcinoma was performed with less than 5% mortality in specialized centers, a textbook outcome was achieved in only approximately 26% of patients. A textbook outcome may be useful for the reporting of patient-level hospital performance and hospital variation, leading to quality improvement efforts after resection of intrahepatic cholangiocarcinoma.
Hydroxychloroquine Retinal Toxicity
Authors: Cinthia Proano, Glenn P Kimball
Journal: New England Journal of Medicine (2019)

A 57-year-old woman receiving long-term hydroxychloroquine treatment presented for ophthalmic evaluation. Achromatic perimetry revealed paracentral scotomas in each eye, and optical coherence tomography revealed a loss of the retinal inner and outer segments.