tbuckley/cabot-search huggingface dataset:
Effectiveness of a Guided Internet- and Mobile-Based Intervention for Patients with Chronic Back Pain and Depression (WARD-BP): A Multicenter, Pragmatic Randomized Controlled Trial
Authors: Harald Baumeister, Sarah Paganini, Lasse Bosse Sander, Jiaxi Lin, Sandra Schlicker, Yannik Terhorst, Morten Moshagen, Jürgen Bengel, Dirk Lehr, David Daniel Ebert
Journal: Psychotherapy and Psychosomatics (2020)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; There is neither strong evidence on effective treatments for patients with chronic back pain (CBP) and depressive disorder nor sufficiently available mental health care offers. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; The aim is to assess the effectiveness of internet- and mobile-based interventions (IMI) as a scalable approach for treating depression in a routine care setting. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This is an observer-masked, multicenter, pragmatic randomized controlled trial with a randomization ratio of 1:1.&lt;b&gt;&lt;i&gt;&lt;/i&gt;&lt;/b&gt;Patients with CBP and diagnosed depressive disorder (mild to moderate severity) were recruited from 82 orthopedic rehabilitation clinics across Germany. The intervention group (IG) received a guided depression IMI tailored to CBP next to treatment-as-usual (TAU; including medication), while the control group (CG) received TAU. The primary outcome was observer-masked clinician-rated Hamilton depression severity (9-week follow-up). The secondary outcomes were: further depression outcomes, pain-related outcomes, health-related quality of life, and work capacity. Biostatistician blinded analyses using regression models were conducted by intention-to-treat and per protocol analysis. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Between October 2015 and July 2017, we randomly assigned 210 participants (IG, &lt;i&gt;n&lt;/i&gt; = 105; CG, &lt;i&gt;n&lt;/i&gt; = 105), mostly with only a mild pain intensity but substantial pain disability. No statistically significant difference in depression severity between IG and CG was observed at the 9-week follow-up (β = –0.19, 95% CI –0.43 to 0.05). Explorative secondary depression (4/9) and pain-related (4/6) outcomes were in part significant (&lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.05). Health-related quality of life was significantly higher in the IG. No differences were found in work capacity. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The results indicate that an IMI for patients with CBP and depression in a routine care setting has limited impact on depression. Benefits in pain and health-related outcomes suggest that an IMI might still be a useful measure to improve routine care.
TBIO-01. SEX DIFFERENCES IN REDOX STATE UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA
Authors: Jasmin Sponagel, Shanshan Zhang, Prakash Chinnaiyan, Joshua Rubin, Joseph Ippolito
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is an aggressive brain tumor in children and adults. It occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that males exhibit a significantly higher abundance of amino acid metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Furthermore, we found that male GBM cell cultures are significantly more sensitive to amino acid deprivation, which was almost entirely driven by amino acids involved in the synthesis of the antioxidant glutathione. Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells exhibited higher levels of GLS1, suggesting they are more dependent on glutamate. Indeed, we found that male GBM cells are more sensitive to pharmacological GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased reactive oxygen species (ROS) in males compared to females. We further confirmed sex differences in redox state through pharmacological depletion of glutathione that resulted in a significant increase in ROS and cell death in male GBM. Together, these data indicate that male GBM cells are more dependent on glutamine to regulate ROS levels. This reveals novel sex-specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.
TBIO-14. CHARACTERISATION OF THE ARGININE PATHWAY ENZYMES IN PAEDIATRIC BRAIN TUMOURS TO DETERMINE SUSCEPTIBILITY TO THERAPEUTIC ARGININE DEPLETION
Authors: Eleanor Bishop, Monika Dimitrova, Lisa Storer, Richard Grundy, Madhumita Dandapani
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Extracellular arginine dependency (auxotrophy) is increasingly being recognised in several tumours. This is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma is known to exhibit this, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. METHODS We used immunohistochemical methods to stain for arginine pathway enzymes in Paediatric High grade glioma (pHGG), low grade glioma (pLGG) and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser Arginase (Arg2), recycling enzymes ornithine transcarbamoylase (OTC), Arginosuccinate synthetase (ASS1) and arginosuccinate lyase (ASL) as well as the transporter SLC7A1. RESULTS Deficiency of OTC, ASS1 and ASL were seen in 92%, 98% and 93% of pHGG samples (n=156) respectively, with deficiency defined as low (&amp;lt;20%) or negative antibody expression. Identical results were seen in pLGG (n=98) - 83%, 97% and 95% were deficient in OTC, ASS1 and ASL. Both pHGG and pLGG highly expressed SLC7A1 and Arg2, demonstrating that they could transport and utilise arginine. In MB (n=82), this auxotrophic signature was again seen in 90% of TMAs with absent or low expression of OTC, ASS1 and ASL and high Arg2 and SLC7A1 expression. CONCLUSIONS These results show that pHGG, pLGG and MB are arginine auxotrophs. Pegylated arginase (BCT-100) is currently in Phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in MB and pLGG.
Human Lung-Resident Macrophages Colocalize with and Provide Costimulation to PD1<sup>hi</sup>Tissue-Resident Memory T Cells
Authors: Mark E. Snyder, John Sembrat, Kentaro Noda, Michael M. Myerburg, Andrew Craig, Nilay Mitash, Takashi Harano, Masashi Furukawa, Joseph Pilewski, John McDyer, Mauricio Rojas, Pablo Sanchez
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Tissue-resident memory T cells (TRM) play a critical role in the defense against inhaled pathogens. The isolation and study of human lung tissue-resident memory T cells and lung-resident macrophages (MLR) are limited by experimental constraints. Objectives: To characterize the spatial and functional relationship between MLR and human lung tissue-resident memory T cells using ex vivo lung perfusion (EVLP). Methods: TRM and MLR were isolated using EVLP and intraperfusate-labeled CD45 antibody. Cells isolated after 6 hours of EVLP were analyzed using spectral flow cytometry. Spatial relationships between CD3+ and CD68+ cells were explored with multiplexed immunohistochemistry. Functional relationships were determined by using coculture and T-cell-receptor complex signal transduction. Measurements and Main Results: Lungs from 8 research-consenting organ donors underwent EVLP for 6 hours. We show that human lung TRM and MLR colocalize within the human lung, preferentially around the airways. Furthermore, we found that human lung CD8+ TRM are composed of two functionally distinct populations on the basis of PD1 (programed cell death receptor 1) and ZNF683 (HOBIT) protein expression. We show that MLR provide costimulatory signaling to PD1hi CD4+ and CD8+ lung TRM,, augmenting the effector cytokine production and degranulation of TRM. Conclusions: EVLP provides an innovative technique to study resident immune populations in humans. Human MLR colocalize with and provide costimulation signaling to TRM, augmenting their effector function.
Cardiac Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging: Finally Up to Speed?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Frans J.Th. Wackers
Journal: Journal of the American College of Cardiology (2010)
US Public Attitudes Toward COVID-19 Vaccine Mandates
Authors: Emily A. Largent, Govind Persad, Samantha Sangenito, Aaron Glickman, Connor Boyle, Ezekiel J. Emanuel
Journal: JAMA Network Open (2020)

Peter G. Szilagyi, MD, MPH; Kyla Thomas, PhD; Megha D. Shah, MD, MPH, MS; Nathalie Vizueta, PhD; Yan Cui, MD, PhD; Sitaram Vangala, MS; Arie Kapteyn, PhD
WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation
Authors: Ning Qing Liu, Michela Maresca, Teun van den Brand, Luca Braccioli, Marijne M. G. A. Schijns, Hans Teunissen, Benoit G. Bruneau, Elphѐge P. Nora, Elzo de Wit
Journal: Nature Genetics (2020)
DIPG-33. CHARACTERIZING THE NEURO-VASCULAR UNIT IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Fatma E El-Khouly, Rianne Haumann, Marjolein Breur, Sophie E M Veldhuijzen van Zanten, Gertjan J L Kaspers, N Harry Hendrikse, Esther Hulleman, Dannis G van Vuurden, Marianna Bugiani
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a median overall survival of eleven months. Lack of chemotherapy efficacy may be related to an intact blood-brain-barrier (BBB). In this study we aim to compare the neuro-vascular unit (NVU) of DIPG to healthy pons tissue. End-stage DIPG autopsy samples (n=5) and age-matched healthy pons samples (n=22), obtained from the NIH NeuroBioBank, were immunohistochemically stained for tight-junction proteins claudin-5 and zonula occludens-1 (ZO-1), basement membrane component laminin, and pericyte marker PDGFRβ. Claudin-5 stains were also used to determine vascular density and diameters. In DIPG, expression of claudin-5 and ZO-1 was reduced, and claudin-5 was dislocated to the abluminal side of endothelial cells. Laminin expression at the glia limitans was reduced in both pre-existent vessels and neovascular proliferation. In contrast to healthy pons, no PDGFRβ expression was detected. The number of blood vessels in DIPG was significantly reduced compared to healthy pons, 13.9±11.8/mm2 versus 26.3±14.2/mm2, respectively (P&amp;lt;0.01). Especially the number of smaller blood vessels (&amp;lt;10µm) was significantly lower (P&amp;lt;0.01). Distribution of larger blood vessels (≥10µm) did not differ between groups (P=0.223). Mean vascular diameter was 9.3±9.9µm for DIPG versus 7.7±9.0µm in healthy pons (P=0.016). Our study demonstrates evidence of structural changes in the NVU in end-stage DIPG. Chemotherapeutic inefficacy could be the result of reduced vascular density. However, further research is needed to determine meaning and extent of these changes and to determine whether these observations are caused by the tumor or the result of treatment.
Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study
Authors: Edwin Jabbari, Shunsuke Koga, Rebecca R Valentino, Regina H Reynolds, Raffaele Ferrari, Manuela M X Tan, James B Rowe, Clifton L Dalgard, Sonja W Scholz, Dennis W Dickson, Thomas T Warner, Tamas Revesz, Günter U Höglinger, Owen A Ross, Mina Ryten, John Hardy, Maryam Shoai, Huw R Morris, Kin Y. Mok, David P. Murphy, Safa Al-Sarraj, Claire Troakes, Steve M. Gentleman, Kieren S.J. Allinson, Zane Jaunmuktane, Janice L. Holton, Andrew J. Lees, Christopher M. Morris, Yaroslau Compta, Ellen Gelpi, John C. van Swieten, Alex Rajput, Leslie Ferguson, Mark R. Cookson, J. Raphael Gibbs, Cornelis Blauwendraat, Jinhui Ding, Ruth Chia, Bryan J. Traynor, Alexander Pantelyat, Coralie Viollet, Bryan J. Traynor, Olga Pletnikova, Juan C. Troncoso, Liana S. Rosenthal, Adam L. Boxer, Gesine Respondek, Thomas Arzberger, Sigrun Roeber, Armin Giese, David J. Burn, Nicola Pavese, Alexander Gerhard, Christopher Kobylecki, P. Nigel Leigh, Alistair Church, Michele T.M. Hu
Journal: The Lancet Neurology (2020)
PATH-20. A CASE REPORT OF NOVEL BCR-ABL1 FUSION IN GLIOBLASTOMA, IDH-WILD TYPE
Authors: Hyungmin Ahn, Kyu Sang Lee, Gheeyoung Choe
Journal: Neuro-Oncology (2020)

Abstract In recent years, molecular tests have become essential to diagnose brain tumor. Although numerous molecular studies of glioblastoma have been conducted, pathogenesis of glioblastoma has not been fully identified. Present report is an extraordinary case of glioblastoma, IDH-wild type with BCR-ABL1 fusion. The BCR-ABL1 fusion is also called ‘Philadelphia gene’ and have never been found in solid tumors other than hemato-lymphoid malignancies. A 63-year-old man presented with clumsy and inappropriate word symptoms a week ago. Magnetic resonance imaging test revealed a 6.6 x 5.0 cm heterogeneously enhancing mass in the left temporal lobe and the patient underwent tumorectomy. Microscopically, tumor showed increasing cellularity, marked nuclear atypia and brisk mitosis. Microvascular proliferation and necrosis was present that can be diagnosis as glioblastoma. In addition, tumor showed strong GFAP positivity which indicated the glial differentiation. There is no evidence of diagnosis as another tumor including metastatic carcinoma or hemato-lymphoid malignancy. Interestingly, BCR-ABL1 fusion was detected in next generation sequencing test. The BCR-ABL1 fusion was a novel finding in glioblastoma, thus additional fluorescence in situ hybridization tests were conducted for confirmation BCR-ABL1 fusion and the same alteration was found. The patient had no leukemic presentation in the blood test, radiologic test and clinical symptom. Notably, this is the first case report that glioblastoma has the BCR-ABL1 fusion.
EXTH-35. SYNERGISTIC EFFECT OF TARGETING THIOREDOXIN REDUCTASE (TRX1) AND DEPLETION OF GLUTATHIONE SYSTEM (GSH) IN GLIOBLASTOMA STEM CELLS
Authors: Fatemeh Jamali, Paul Daniel, Kevin Petrecca, Bassam Abdulkarim, Siham Sabri
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM), the most common and advanced malignant primary brain tumor in adults remains incurable. GBM tumor recurrence occurs within a short time reflecting the failure to eradicate chemo-radioresistant GBM stem cells (GSCs). GSCs alter the redox system including Thioredoxin (Trx) and glutathione (GSH) systems to counteract increased reactive oxygen species (ROS). We previously showed the role of O6-methylguanine-DNA methyltransferase (MGMT) in response to PRIMAMET, a drug that targets the TP53 tumor suppressor gene and decrease Thioredoxin reductase1 (TRxR1) levels and further identified a positive relationship between MGMT and TrxR1 in established GBM cell lines isogenic for MGMT. Auranofin (Au), an orally available ROS-inducing FDA-approved drug is a potent irreversible inhibitor of TrxR1. The effect of Au on GSCs and the potential relationship between TrXR1, MGMT and p53 specifically in GSCs remain unknown. We hypothesized that increased ROS levels in GSCs might affect their drug resistant phenotype. we investigated the cytotoxic effects of Au on GSCs with known MGMT and P53 status and the mechanisms underlying these effects. Our results suggest that Au exerts strong cytotoxic effects in GSCs within a micromolar range. These effects were associated with increased ROS levels, decreased TrXR1, MGMT, phosphorylation of ERk1/2, activation of p53 and increased apoptosis, we also used a knockdown strategy to assess the role of p53 and showed that increased sensitivity to Au for p53-knockdown. We showed the role of ROS in response to Au using ROS inducer L-Buthionine Sulfoxamine (L-BSO), a GSH inhibitor, and ROS scavenger N-Acetylcysteine (NAc). L-BSO combined with Au drastically decreased the IC50 within a nanomolar range suggesting the crucial role of both Trx and GSH systems in GSCs redox balance. Increased ROS with concomitant GSH depletion using L-BSO might circumvent drug-induced oxidative stress and overcome drug resistance in MGMT-positive and negative GSCs
IMMU-21. THE COMBINATION OF DELTA-24-ACT WITH AN IMMUNE CHECKPOINT INHIBITOR RESULTS IN ANTI-GLIOMA EFFECT AND IMMUNE MEMORY
Authors: Montserrat Puigdelloses, Virginia Laspidea, Marc Garcia-Moure, Daniel De la Nava, Dolores Hambardzumyan, Zhihong Chen, Sara Labiano, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gállego-pérez de Larraya, Marta M Alonso
Journal: Neuro-Oncology (2020)

Abstract Oncolytic viruses have become promising therapeutic candidates to treat gliomas. Our group has developed Delta-24-ACT, an oncolytic adenovirus armed with the positive costimulatory ligand 4-1BBL which is capable to trigger the activation of T cells and thereby increase their antitumor immune response. Here we evaluate the anti-glioma effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor. We observed that Delta-24-ACT was able to infect and kill murine glioma (GL261-5 and CT-2A) and also human glioma cell lines (U87-MG and U251-MG), while maintaining its replication in the latter. Of importance, Delta-24-ACT infection resulted in 4-1BBL expression on the membrane of glioma cells. Moreover, this ligand was functional and was able to stimulate CD8 lymphocytes in vitro, suggesting the potential of Delta-24-ACT to trigger an effective immune response. Furthermore, in vivo Delta-24-ACT showed anti-tumour effect in two murine glioma models by significantly increasing the median survival time and leading to long-term survivors. Mechanistic studies demonstrated an increase of the T cell infiltration and the activation of different immune cell populations by flow cytometry and a decrease of proliferative cells and tumour vessels by immunohistochemistry on FFPE brain samples. Importantly, the infiltrating lymphocytes also showed signs of exhaustion increasing the amount of IL-10 and the expression of PD-1. To overcome this exhaustion we combined Delta-24-ACT with an anti-PD-1 antibody. Evaluation of this combination in vivo further increased the median survival time of treated tumor-bearing mice and resulted in 50% long-term survivors. Rechallenge studies with the same cell line showed that combination treatment effectively protected these animals of developing tumors and therefore, the acquisition of immune memory. In summary, our data demonstrated that Delta-24-ACT induces a potent anti-tumour effect in vitro and in vivo as a result of the recruitment of immune cell populations modulating the immunosuppressive tumour microenvironment of glioma.
Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors
Authors: Marie-A Chaix, Neha Parmar, Caroline Kinnear, Myriam Lafreniere-Roula, Oyediran Akinrinade, Roderick Yao, Anastasia Miron, Emily Lam, Guoliang Meng, Anne Christie, Ashok Kumar Manickaraj, Stacey Marjerrison, Rejane Dillenburg, Mylène Bassal, Jane Lougheed, Shayna Zelcer, Herschel Rosenberg, David Hodgson, Leonard Sender, Paul Kantor, Cedric Manlhiot, James Ellis, Luc Mertens, Paul C. Nathan, Seema Mital
Journal: JACC CardioOncology (2020)

Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging.This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors.We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed.Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10-15). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes.Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778).
Complications of nasal and pharyngeal swabs: a relevant challenge of the COVID-19 pandemic?
Authors: Bandik Föh, Max Borsche, Alexander Balck, Stefan Taube, Jan Rupp, Christine Klein, Alexander Katalinic
Journal: European Respiratory Journal (2020)

<b>Although swab procedures during SARS-CoV-2 testing are generally safe (3 adverse events in 11 476 swab procedures; 0.026%), increased awareness of complications is necessary, considering approximately 5.1 million tests conducted worldwide daily.</b>https://bit.ly/2J5sd96
Defining Clinical Utility of Tumor Biomarker Tests: A Clinician's Viewpoint
Authors: Daniel F. Hayes
Journal: Journal of Clinical Oncology (2020)

Tumor biomarker tests (TBTs) are used to guide therapeutic strategies for patients with cancer. However, the regulatory environment for TBTs in the United States is inconsistent and, in general, TBTs are poorly valued. The National Academy of Medicine has recommended that TBTs should not be used in general practice until they are shown to have analytical validity and clinical utility. The latter term, first coined by the Evaluation of Genomic Applications in Practice and Prevention Initiative, has been widely stated but is indeterminately defined. In considering whether a TBT has clinical utility, several factors need to be considered: (1) What is the intended use of the TBT? (2) What are the end points that are used to determine clinical utility? (3) How substantial does the difference in end points between groups defined by the TBT need to be to determine therapeutic strategies? (4) What is the risk tolerance of the stakeholders? and (5) Who are the stakeholders that make the decision? For all these factors, the data used to consider clinical utility must be derived from level I evidence studies. In conclusion, there is no strict definition of clinical utility for a TBT. However, consideration of these factors will lead to more objective conclusions. Doing so will facilitate value-based decisions regarding whether a TBT should be used to guide patient care.