tbuckley/cabot-search huggingface dataset:
Frailty subtypes and recovery in older survivors of acute respiratory failure: a pilot study
Authors: Matthew R Baldwin, Lauren R Pollack, Richard A Friedman, Simone P Norris, Azka Javaid, Max R O'Donnell, Matthew J Cummings, Dale M Needham, Elizabeth Colantuoni, Mathew S Maurer, David J Lederer
Journal: Thorax (2020)

Identifying subtypes of acute respiratory failure survivors may facilitate patient selection for post-intensive care unit (ICU) follow-up clinics and trials.We conducted a single-centre prospective cohort study of 185 acute respiratory failure survivors, aged ≥ 65 years. We applied latent class modelling to identify frailty subtypes using frailty phenotype and cognitive impairment measurements made during the week before hospital discharge. We used Fine-Gray competing risks survival regression to test associations between frailty subtypes and recovery, defined as returning to a basic Activities of Daily Living disability count less than or equal to the pre-hospitalisation count within 6 months. We characterised subtypes by pre-ICU frailty (Clinical Frailty Scale score ≥ 5), the post-ICU frailty phenotype, and serum inflammatory cytokines, hormones and exosome proteomics during the week before hospital discharge.We identified five frailty subtypes. The recovery rate decreased 49% across each subtype independent of age, sex, pre-existing disability, comorbidity and Acute Physiology and Chronic Health Evaluation II score (recovery rate ratio: 0.51, 95% CI 0.41 to 0.63). Post-ICU frailty phenotype prevalence increased across subtypes, but pre-ICU frailty prevalence did not. In the subtype with the slowest recovery, all had cognitive impairment. The three subtypes with the slowest recovery had higher interleukin-6 levels (p=0.03) and a higher prevalence of ≥ 2 deficiencies in insulin growth factor-1, dehydroepiandrostersone-sulfate, or free-testosterone (p=0.02). Exosome proteomics revealed impaired innate immunity in subtypes with slower recovery.Frailty subtypes varied by prehospitalisation frailty and cognitive impairment at hospital discharge. Subtypes with the slowest recovery were similarly characterised by greater systemic inflammation and more anabolic hormone deficiencies at hospital discharge.
IMMU-16. INTRA-TUMOURAL IL-12 DELIVERY ENABLES CAR T-CELL IMMUNOTHERAPY FOR HIGH-GRADE GLIOMA
Authors: Giulia Agliardi, Anna Rita Liuzzi, Alastair Hotblack, Donatella De Feo, Nicolás Núñez, Ekaterina Friebel, Francesco Nannini, Thomas Roberts, Rajiv Ramasawmy, Cassandra Stowe, Iwan Williams, Bernard Siow, Mark Lythgoe, Tammy Kalber, Sergio Quezada, Martin Pule, Sonia Tugues, Burkhard Becher, Karin Straathof
Journal: Neuro-Oncology (2020)

Abstract Treatment with T-cells redirected to tumour specificity with a chimeric antigen receptor (CAR) may be well suited to treat intracranial tumours due to the ability of T-cells to access the central nervous system and migrate to infiltrative sites of disease. In adult glioblastoma, a case report of local and distant eradication of intracranial and spinal tumour deposits following intraventricular infusion of IL13Ra2-CAR T-cells indicates the potential of this approach. However, in contrast to the sustained complete remissions observed in haematological malignancies, in the majority of patients with glioblastoma CAR T-cell therapy has not resulted in clinical benefit. Tumour heterogeneity and the highly immune inhibitory tumour microenvironment (TME) are likely key barriers to achieving durable anti-tumour immunity. Here use intra-tumoural administration of IL-12 to enable CAR T-cell immunity. We employed CAR-T cells targeting the tumour-specific epidermal growth factor variant III (EGFRvIII). In an immunocompetent orthotopic mouse model of high-grade glioma, we show that CAR-T cells alone failed to control fully established tumour, but when combined with a single, locally delivered dose of IL-12, durable antitumor responses were achieved. IL-12 not only boosted cytotoxicity of CAR T-cells, but also reshaped the TME driving increased infiltration of proinflammatory CD4+ T-cells, decreased numbers of regulatory T-cells (Tregs) and activation of the myeloid compartment. Critically, immunotherapy enabling benefits of IL-12 were achieved with minimal systemic effects. Our findings show that local delivery of IL-12 is an effective adjuvant for CAR-T cell therapy for high-grade glioma. Assessment of application in high-risk childhood brain tumours is ongoing.
Paravalvular Regurgitation According to Transcatheter Aortic Valve Prosthesis Type
Authors: Georg Stachel, Mohamed Abdel-Wahab, Suzanne de Waha-Thiele, Steffen Desch, Hans-Josef Feistritzer, Mitsunobu Kitamura, Ingo Eitel, Thomas Kurz, Holger Thiele
Journal: JACC. Cardiovascular imaging (2020)
Gut Microbiome Components Predict Response to Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer: A Prospective, Longitudinal Study
Authors: Yuxi Yi, Lijun Shen, Wei Shi, Fan Xia, Hui Zhang, Yan Wang, Jing Zhang, Yaqi Wang, Xiaoyang Sun, Zhiyuan Zhang, Wei Zou, Wang Yang, Lingyi Zhang, Ji Zhu, Ajay Goel, Yanlei Ma, Zhen Zhang
Journal: Clinical Cancer Research (2020)

The gut microbiome is involved in antitumor immunotherapy and chemotherapy responses; however, evidence-based research on the role of gut microbiome in predicting response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) remains scarce. This prospective, longitudinal study aimed to evaluate the feasibility of the gut microbiome in predicting nCRT responses.We collected 167 fecal samples from 84 patients with LARC before and after nCRT and 31 specimens from healthy individuals for 16S rRNA sequencing. Patients were divided into responders and nonresponders according to pathologic response to nCRT. After identifying microbial biomarkers related to nCRT responses, we constructed a random forest classifier for nCRT response prediction of a training cohort of baseline samples from 37 patients and validated the classifier in another cohort of 47 patients.We observed significant microbiome alterations represented by a decrease in LARC-related pathogens and an increase in Lactobacillus and Streptococcus during nCRT. Furthermore, a prominent microbiota difference between responders and nonresponders was noticed in the baseline samples. Microbes related with butyrate production, including Roseburia, Dorea, and Anaerostipes, were overrepresented in responders, whereas Coriobacteriaceae and Fusobacterium were overrepresented in nonresponders. Ten biomarkers were selected for the response-prediction classifier, including Dorea, Anaerostipes, and Streptococcus, which yielded an area under the curve value of 93.57% [95% confidence interval (CI), 85.76%-100%] in the training cohort and 73.53% (95% CI, 58.96%-88.11%) in the validation cohort.The gut microbiome offers novel potential biomarkers for predicting nCRT responses, which has important manifestations in the clinical management of these patients.
DDRE-16. SYNERGISTIC TUMOR SUPPRESSION FROM COMBINATION OF ONC201 AND EPIGENETIC MODULATORS EZH2 OR HDAC INHIBITOR PROVIDES A NOVEL TREATMENT STRATEGY FOR GBM AND DMG
Authors: Yiqun Zhang, Lanlan Zhou, Safran Howard, Attila Seyhan, Wafik El-Deiry
Journal: Neuro-Oncology (2020)

Abstract ONC201 is a promising anti-cancer agent that kills tumor cells by triggering an integrated stress response (ISR) dependent on ATF4. ONC201 demonstrated tumor regression and prolonged disease stability in patients with histone H3K27M-mutated midline glioma. The Enhancer of Zeste Homolog 2 (EZH2), a subunit of the polycomb repressive complex 2 (PRC2), is a histone methyltransferase that tri-methylates H3K27 (H3K27me3) and silences target genes. EZH2 inhibitors (EZH2i) reduce global H3K27 methylation. Based on the fact that the H3K27 mutation reduces H3K27 dimethylation (H3K27me2) and trimethylation (H3K27me3), we hypothesized that ONC201 sensitivity and tumor cell death may be enhanced by reducing H3K27 methylation with EZH2i as a mimic of H3K27M-mutation and by increasing H3K27 acetylation with histone deacetylase inhibitors (HDACi). We evaluated synergy of EZH2i EPZ-6438 or HDACi vorinostat with ONC201 against GBM cell lines, U251 and T98G-1 and DMG cell line, SF8638. Cell viability was determined with the Cell Titer Glo assay. Apoptosis was evaluated through immunoblotting of cleaved PARP and flow cytometry analysis of cell distribution. ISR activity was evaluated using immunoblotting of ATF4. Our result demonstrate that ONC201 synergistically reduced cell viability with vorinostat in U251, T98G-1 and SF8628 cell lines, induced apoptosis in combination with vorinostat in U251 and SF8628. ONC201 synergistically reduced cell viability and induced apoptosis with EPZ-6438 in U251. The immunoblotting detected no enhancement of ATF4 by addition of EPZ-6438 to ONC201. Immunoblotting analysis showed that EPZ-6438 reduced H3K27me3 in U251. Our results unravel potent synergy between ONC201 and EZH2i or HDACi in GBM and DMG cell lines, and provide further insights into the role of H3K27me3 in ONC201 drug sensitivity.
Abstract 12272: Prediction of Responsiveness of Immunoadsorption Therapy by Analyzing Anti-Heart Autoantibodies and Cardiodepressive Activity in Patients With Dilatative Cardiomyopathy
Authors: Bishwas Chamling, Alida L Caforio, Mara Seguso, Nicoletta Gallo, Yvonne Reinke, Stefan Gross, Karin Klingel, Marcus Dörr, Jens Fielitz, Stephan B Felix
Journal: Circulation (2018)

Introduction: Anti-heart antibodies (AHA) are found in a subset of patients with dilated cardiomyopathy (DCM) and are thought to have a functional role in the development and course of the disease....
Tumor targeting using magnetic nanoparticle
Authors: M. Shevtsov, L. Yakovleva, B. Nikolaev, Y. Marchenko, A. Dobrodumov, K. Onokhin, Y. Onokhina, S. Selkov, A. Mikhrina, I. Guzhova, M. Martynova, O. Bystrova, A. Ischenko, B. Margulis
Journal: Neuro-Oncology (2014)
PATH-15. DEEP LEARNING ENABLED PREDICTION OF ISOCITRATE DEHYDROGENASE MUTATION STATUS FROM DIGITAL HISTOPATHOLOGY DATA IN GLIOBLASTOMA
Authors: Sied Kebir, Tobias Blau, Lazaros Lazaridis, Teresa Schmidt, Kathy Keyvani, Ulrich Sure, Martin Stuschke, Christoph Kleinschnitz, Björn Scheffler, Martin Glas
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The determination of isocitrate dehydrogenase (IDH) mutation status plays a crucial role in the diagnosis of glioblastoma. Depending on the age of the patient and the result of the immunohistochemical analysis, additional DNA sequencing may be required to determine IDH mutation status. As DNA sequencing results can occasionally take several days until available, there is a need for inexpensive and fast non-invasive methods. In this work, we investigated whether IDH mutation detection by artificial intelligence (deep learning) from digitized hematoxylin-eosin (H&amp;E) stained sectional specimens is feasible. METHODS Patients with histologically confirmed glioblastoma from The Cancer Genome Atlas cohort were included if digitized H&amp;E stained whole-slide scans with corresponding information on IDH status were publicly available. The total cohort was subdivided into a training, validation, and test cohort in a ratio of 44:33:23. Whole-slide scans were partitioned into tiles of fixed size and used to train a Resnet-34 convolutional neural network. The evaluation of the trained model was performed once on the test cohort using Receiver Operating Characteristic analysis and Area-Under-The-Curve (AUC) metric. To ascertain which regions of the H&amp;E specimens were decisive for the determination of IDH status, the Grad-CAM method was used. RESULTS 124 patients were included, 29 of which were IDH mutant. The digitized H&amp;E slides had an average size of 2.5 gigabytes per image file and approximately 1000 tiles per slide were prepared. The prediction AUC of the trained model was 0.94. The duration of IDH prediction was about 3.5 seconds per slide. The Grad-CAM evaluation confirmed that the model mainly used cellular regions to collect decision-supporting information. CONCLUSIONS This pilot study shows the promising potential of deep learning for the prediction of IDH mutation status from digitized H&amp;E scans in glioblastoma. To confirm these data, testing this model on an independent cohort is needed.
TMOD-31. NOVEL GENETIC CHARACTERIZATION OF MURINE MEDULLOBLASTOMA CELL LINES
Authors: Sarah Rumler, Mark Maienschein-Cline, Melline Fontes Noronha, Fei Song, Andrew Lock, Jeffrey Loeb, M Kelly Nicholas
Journal: Neuro-Oncology (2020)

Abstract Pre-clinical research in medulloblastoma (MB) is conducted either with human-derived cell lines or tumors arising in genetically engineered mice (GEM). Murine MB cell lines are not readily available. To begin in vitro immuno-oncology MB research, we identified murine MB cell lines from research laboratories to determine their fidelity to human cell lines and GEM models. Using PubMed, we identified murine MB cell lines of potential interest. Seven cell lines form two independent laboratories were identified. We characterized the cell lines’ behavior in culture and performed next generation sequencing (NGS) on four of them (two from each group) to determine the extent to which these cell lines resemble both human and GEM MB models. DNA and RNA were extracted from MB cell lines, quality and quantity assessed. Whole-exome sequencing was performed and post-capture libraries sequenced. The cell lines identified were derived from either FVB/N TP53 null mice carrying the N-MYC oncogene (GTML3 and GTML5) or C57Bl6/J TP53 null heterozygous ptch (-/+) mice (MM1 and MM3). GTML cells grow in suspension and form clusters. MM cells are adherent, growing in monolayers. Whole exome sequencing of the 4 lines revealed similarities between both GEM and human MB cell lines, demonstrating 25% of sixteen genes known to be affected in both GEM tumors and human MB cell lines. Furthermore, the four cell Iines shared five deleterious mutations previously not described in MB, suggesting they might play a role in MB tumorigenesis: Pde4d, Whrln, Olr156, RIKEN cDNA D630045J12, and Olfr159. These are the first data to describe these murine MB cell lines and demonstrates 1) they resemble both GEM tumors and human MB cell lines at the genome level, and 2) they offer the potential to identify heretofore unrecognized mechanisms in MB tumorigenesis.
Dynamic CTCF binding directly mediates interactions among <i>cis</i>-regulatory elements essential for hematopoiesis
Authors: Qian Qi, Li Cheng, Xing Tang, Yanghua He, Yichao Li, Tiffany Yee, Dewan Shrestha, Ruopeng Feng, Peng Xu, Xin Zhou, Shondra Pruett-Miller, Ross C. Hardison, Mitchell J. Weiss, Yong Cheng
Journal: Blood (2020)
The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas
Authors: Bidisha Bhattacharya, Shiqi Xiao, Sujoy Chatterjee, Michael Urbanowski, Alvaro Ordonez, Elizabeth A. Ihms, Garima Agrahari, Shichun Lun, Robert Berland, Alexander Pichugin, Yuanwei Gao, John Connor, Alexander R. Ivanov, Bo-Shiun Yan, Lester Kobzik, Bang-Bon Koo, Sanjay Jain, William Bishai, Igor Kramnik
Journal: Journal of Clinical Investigation (2020)

The mechanism by which only some individuals infected with Mycobacterium tuberculosis develop necrotic granulomas with progressive disease while others form controlled granulomas that contain the infection remains poorly defined. Mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human tuberculosis (TB) granulomas, which are linked to macrophage dysfunction, while their congenic counterpart (B6) mice do not. In this study we report that (a) sst1S macrophages developed aberrant, biphasic responses to TNF characterized by superinduction of stress and type I interferon pathways after prolonged TNF stimulation; (b) the late-stage TNF response was driven via a JNK/IFN-β/protein kinase R (PKR) circuit; and (c) induced the integrated stress response (ISR) via PKR-mediated eIF2α phosphorylation and the subsequent hyperinduction of ATF3 and ISR-target genes Chac1, Trib3, and Ddit4. The administration of ISRIB, a small-molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of M. tuberculosis–infected sst1S mice and concomitantly reduced the bacterial burden. Hence, induction of the ISR and the locked-in state of escalating stress driven by the type I IFN pathway in sst1S macrophages play a causal role in the development of necrosis in TB granulomas. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel host-directed therapy strategies.
Additional Lipid Lowering Trials Using Surrogate Measurements of Atherosclerosis by Carotid Intima-Media Thickness: More Clarity or Confusion?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Evan A. Stein
Journal: Journal of the American College of Cardiology (2008)
Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease
Authors: Kasper W. ter Horst, Daniel F. Vatner, Dongyan Zhang, Gary W. Cline, Mariette T. Ackermans, Aart J. Nederveen, Joanne Verheij, Ahmet Demirkiran, Bart A. van Wagensveld, Geesje M. Dallinga-Thie, Max Nieuwdorp, Johannes A. Romijn, Gerald I. Shulman, Mireille J. Serlie
Journal: Diabetes Care (2020)

Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans.
Abstract 12865: Data-Driven Approach for Coronary Vessel Reconstruction
Authors: Kritika Iyer, Christopher J Arthurs, Cyrus P Najarian, Reza Soroushmehr, Brahmajee K Nallamothu, C. Alberto Figueroa
Journal: Circulation (2019)

Introduction: This study aims to develop a semi-automated method to reconstruct the 3D geometry of the coronary arteries using machine learning. Reconstruction of coronary arteries could assist wit...
Abstract 723: Cardiomyocyte GATA4 Regulates Angiogenesis in the Adult Mouse Heart
Authors: Joerg Heineke, Michelle Sargent, Jian Xu, Toru Oka, Jeffery D Molkentin
Journal: Circulation (2006)

Introduction: GATA4 is a cardiac transcription factor that plays an important role in cardiac embryonic development and the induction and maintenance of postnatal heart growth and cardiomyocyte sur...
Advancing Practice Science With Electronic Health Record Use Data
Authors: Christine Sinsky
Journal: JAMA Internal Medicine (2020)

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<i>QuickStats:</i> Death Rates* from Stroke† Among Persons Aged ≥65 Years, by Sex and Age Group — National Vital Statistics System, United States, 2018
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Age group (yrs) 75-84 ≥85 Deaths per 100,000 population Total Men Women * With 95% confidence intervals shown with error bars.Rates are per 100,000 population in each age group.† Deaths attributed to stroke (cerebrovascular diseases) were identified using the International Classification of Diseases, Tenth Revision underlying cause of death codes I60-I69.In 2018, the death rate from stroke was 242.7 per 100,000 persons aged ≥65 years.Persons aged ≥85 years had the highest death rate from stroke (984.3),followed by those aged 75-84 years (256.0)and those aged 65-74 years (76.8).For both men and women, the death rates increased with age.The death rate for women (261.6) was higher than that for men (219.0) for persons aged ≥65 years, but men had higher stroke death rates for the 65-74 and 75-84 age groups.Women aged ≥85 years had higher death rates than did men in this age group.
ETMR-02. NOVEL CIC-LEUTX FUSION IN CNS EMBRYONAL TUMOR: A CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Wanming Hu, Juan Wang, Xing Zhang, Yuhang Ji, Chao Song, Xiaofei Sun
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Central nervous system (CNS) embryonal tumor is a group of rare, poorly differentiated neuroepithelial malignant neoplasm predominantly occurs in pediatrics. Herein, we firstly report a CNS embryonal tumor harboring pathogenic CIC-LEUTX fusion. METHODS Immunohistochemistry (IHC), Fluorescence in Situ Hybridization (FISH) and Next Generation sequencing (NGS). RESULTS A 2-year-old male was found to have solid and cystic mass in left temporal lobe-basal ganglia and left parietal lobe (maximum diameter=75mm). The pathological diagnosis was CNS embryonal tumor (NEC) after totally resection. The tumor was poorly differentiated embryonal neoplasms of neuroectodermal origin that lacked the specific features and rosettes. IHC showed Syn was strongly/diffusely positive and Ki67 proliferation index was high (50%+), and copy number at the 19q13.42 C19MC locus showed no alterations. NGS showed pathogenic mutations including a brand new CIC-LEUTX fusion, heterozygous germline NBN c.C127T mutation and somatic TSC2 c.G2714A mutation. One month after operation, intracranial tumor recurred (maximum diameter=55mm) and spinal cord implantation metastasis occurred, and then the patient received chemotherapy (CTX+CBP+VCR/DDP+VP-16) and had significant improvement in symptoms and tumor shrinkage (maximum diameter=31mm). Literature review revealed CIC fusion predominantly presented in sarcomas, such as CIC-NUTM1 fusion in rare CNS sarcoma, CIC-LEUTX fusion in epithelioid angiosarcoma and CIC-DUX4 fusion in Ewing-like sarcoma. Hitherto, apart from this case, there were only two cases which had CIC-LEUTX fusion in CNS, including a case of CNS angiosarcoma and a case of anaplastic ganglioglioma. CONCLUSIONS We firstly found a specific new type in CNS embryonal tumor with distinct molecular-pathological characteristics of CIC-LEUTX fusion.