tbuckley/cabot-search huggingface dataset:
Global, regional, and national estimates of target population sizes for covid-19 vaccination: descriptive study
Authors: Wei Wang, Qianhui Wu, Juan Yang, Kaige Dong, Xinghui Chen, Xufang Bai, Xinhua Chen, Zhiyuan Chen, Cécile Viboud, Marco Ajelli, Hongjie Yu
Journal: BMJ (2020)

To provide global, regional, and national estimates of target population sizes for coronavirus disease 2019 (covid-19) vaccination to inform country specific immunisation strategies on a global scale.Descriptive study.194 member states of the World Health Organization.Target populations for covid-19 vaccination based on country specific characteristics and vaccine objectives (maintaining essential core societal services; reducing severe covid-19; reducing symptomatic infections and stopping virus transmission).Size of target populations for covid-19 vaccination. Estimates use country specific data on population sizes stratified by occupation, age, risk factors for covid-19 severity, vaccine acceptance, and global vaccine production. These data were derived from a multipronged search of official websites, media sources, and academic journal articles.Target population sizes for covid-19 vaccination vary markedly by vaccination goal and geographical region. Differences in demographic structure, presence of underlying conditions, and number of essential workers lead to highly variable estimates of target populations at regional and country levels. In particular, Europe has the highest share of essential workers (63.0 million, 8.9%) and people with underlying conditions (265.9 million, 37.4%); these two categories are essential in maintaining societal functions and reducing severe covid-19, respectively. In contrast, South East Asia has the highest share of healthy adults (777.5 million, 58.9%), a key target for reducing community transmission. Vaccine hesitancy will probably impact future covid-19 vaccination programmes; based on a literature review, 68.4% (95% confidence interval 64.2% to 72.6%) of the global population is willing to receive covid-19 vaccination. Therefore, the adult population willing to be vaccinated is estimated at 3.7 billion (95% confidence interval 3.2 to 4.1 billion).The distribution of target groups at country and regional levels highlights the importance of designing an equitable and efficient plan for vaccine prioritisation and allocation. Each country should evaluate different strategies and allocation schemes based on local epidemiology, underlying population health, projections of available vaccine doses, and preference for vaccination strategies that favour direct or indirect benefits.
DIPG-20. DETERMINATION AND MANAGEMENT OF HYDROCEPHALUS IN PATIENTS WITH DIPG, AN INSTITUTIONAL EXPERIENCE
Authors: Adriana Fonseca, Palma Solano-Paez, Michal Zapotocky, Ute Bartels, Eric Bouffet
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The is no consensus in best practices for the management of hydrocephalus in patients with Diffuse Intrinsic Pontine Glioma (DIPG). To date, the impact on survival of hydrocephalus and Cerebro-Spinal Fluid (CSF) diversion in this population remains to be elucidated. Herein, we describe our institutional experience. METHODS Patients with a clinical and radiological diagnosis of DIPG were identified at the Hospital for Sick Children between 2000–2019. Images at diagnosis and at disease progression were assessed for hydrocephalus using the frontal-occipital ratio (FOR) method. Proportional hazard analyses were used to identify factors correlated with survival. RESULTS Eighty-nine consecutive patients diagnosed with DIPGs were treated at our institution. At diagnosis, 29% (n=26) of patients presented with hydrocephalus, seven patients underwent CSF diversion. Out of the remaining nineteen patients, n=6 had stable or improved hydrocephalus in follow-up scans, n=6 had persistent hydro and n=2 required CSF diversion at the time of disease progression. Seven did not undergo a follow-up scan. Out of sixty-five patients with imaging at the time of progression, fifty-five percent of patients (n=36) presented with hydrocephalus and ten of them required CSF diversion. On univariate analysis, the presence of hydrocephalus or CSF diversion at diagnosis and/or did not correlate with a survival advantage. CONCLUSIONS CSF diversion for the management of hydrocephalus in patients with DIPG does not impact survival and in some cases resolves spontaneously after the initiation of radiotherapy and steroids. This observation needs to be validated in a prospective cohort.
COVD-31. THE STATE OF NEURO-ONCOLOGY DURING THE COVID-19 PANDEMIC: A WORLDWIDE ASSESSMENT
Authors: Maciej Mrugala, Quinn Ostrom, Shelley Pressley, Alissa Thomas, Jeffrey S Wefel, Scott Coven, Alvina Acquaye, Chas Haynes, Sameer Agnihotri, Michael Lim, Katherine Peters, Nicholas Butowski, Shawn Hervey-Jumper, Alyx Porter, Kathy Oliver, Erin Dunbar, Jennie Taylor, David Schiff, Farshad Nassiri, Monika Hegi, Terri Armstrong, Martin van den Bent, Susan Chang, Gelareh Zadeh, Milan Chheda
Journal: Neuro-Oncology (2020)

Abstract To assess the impact of the pandemic on the field, we performed an international web-based survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents from April 24 through May 17. Of 582 respondents, 258 (45%) were in the US, and 314 (55%) were international. 80.4% were affiliated with academic institutions. 94% respondents reported changes in clinical practice; 95% reported conversion to telemedicine for at least some appointments. However, almost 10% practitioners felt the need to see patients in person specifically because of billing concerns and perceived institutional pressure. Over 50% believed neuro-oncology patients were at increased risk of contracting COVID-19. 67% practitioners suspended enrollment for at least one clinical trial: 53% suspended phase II and 62% suspended phase III trial enrollment. 71% clinicians feared for their or their families’ safety, specifically because of their clinical duties. 20% percent said they did not have enough PPE to work safely; about the same percentage were unhappy with their institutions’ response to the pandemic. 43% believed the pandemic would negatively affect their academic career, and 52% fellowship program directors were worried about losing funding for their training programs. While 69% respondents reported increased stress, 44% were offered no psychosocial support. 37% had their salary reduced. 36% researchers had to temporarily close their laboratories. In contrast, the pandemic created positive changes in perceived patient and family satisfaction, quality of communication, and use of technology to deliver care and interactions with other practitioners. CONCLUSIONS: The pandemic has altered standard treatment schedules and limited investigational treatment options for patients. In some cases, clinicians felt institutional pressure to continue conducting billable in-person visits when telemedicine visits would have sufficed. A lack of institutional support created anxiety among clinicians and researchers. We make specific recommendations to guide clinical and scientific infrastructure moving forward.
TLR2-mediated innate immune priming boosts lung anti-viral immunity
Authors: Jason Girkin, Su-Ling Loo, Camille Esneau, Steven Maltby, Francesca Mercuri, Brendon Chua, Andrew T. Reid, Punnam Chander Veerati, Chris L. Grainge, Peter A.B. Wark, Darryl Knight, David Jackson, Christophe Demaison, Nathan W. Bartlett
Journal: European Respiratory Journal (2020)

Background We assessed whether Toll-like receptor (TLR)2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases. Methods We employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III interferon (IFN) production, as well as the lung tissue and epithelial cell immune transcriptome. Results We show, in vivo , that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7 days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1 day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7 days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro , INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for nuclear factor (NF)-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response. Conclusion Airway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.
Simultaneous Detection of Single Nucleotide Variants and Expression of RNA and Protein in Multiple Myeloma Bone Marrow Aspirates
Authors: David G. Coffey, Katherine A. Lombardo, Andrea M.H. Towlerton, MaryCatherine A. Farwell, Gokhan Demirkan, Gavin Meredith, Rhonda Meredith, Damian J. Green, Edus H. Warren
Journal: Blood (2017)
Myeloid Mixed Chimerism and Relapse in Myelofibrosis after Allogeneic Stem Cell Transplant
Authors: Samer A. Srour, Parth Desai, Stefan O. Ciurea, Qaiser Bashir, Betul Oran, Amanda L. Olson, Sairah Ahmed, Prithviraj Bose, Rohtesh S. Mehta, Naveen Pemmaraju, Srdan Verstovsek, Richard E Champlin, Uday Popat
Journal: Blood (2017)
Abstract 10743: Lipoprotein Insulin Resistance Score, but Not Traditional Measures, Discriminates Patients With Pre-operative Metabolic Syndrome at up to One Year Following Bariatric Surgery
Authors: Ruina Zhang, BingXue Lin, Manish Parikh, Edward A Fisher, Jeffrey S Berger, Jose O Aleman, Sean P Heffron
Journal: Circulation (2019)

Lipoprotein insulin resistance (LPIR) is a composite biomarker representative of atherogenic dyslipidemia characteristic of early insulin resistance. Clinically, it is elevated in obesity and may p...
LGG-29. TREATMENT FOR RECURRENT OPTIC PATHWAY PILOCYTIC ASTROCYTOMA
Authors: Masahiro Nonaka, Mayuko Miyata, Natsumi Yamamura, Akio Asai
Journal: Neuro-Oncology (2020)

Abstract Chemotherapy after biopsy or partial resection of the tumor is widely accepted as first-line therapy for optic pathway pilocytic astrocytoma. However, there is no standard of care for recurred tumors. We investigated our cases which showed recurrence after initial therapy. Retrospective analysis of four recurrent optic pathway pilocytic astrocytoma cases was performed. All patients underwent partial resection or biopsy of the tumor, and all received carboplatin and etoposide- based chemotherapy as initial treatment. Mean age at first therapy was 2.3 years old, and mean time from initial therapy to recurrence of the tumor was 5.6 years. Two patients were totally blind at the time of recurrence, and other two had partial visual field losses. One patient underwent total resection of the tumor, and other three patients underwent partial resection followed by chemotherapy. Visual function in patients with visual acuity did not deteriorate after removal of the recurrent tumor. There was no recurrence of the tumor who underwent total resection. All of the three patients who had partial resection followed by chemotherapy recurred. Mean time from first recurrence to second recurrence was 1.8 years. After second recurrence, all patients underwent radiation therapy. One patient died due to malignant transformation of the tumor. For recurrent optic pathway pilocytic astrocytoma, prognosis may be better if total resection of the tumor without deteriorating the vision is possible.
MBCL-32. HIGH-DOSE CHEMOTHERAPY WITH STEM CELL RESCUE FOR RECURRENT PREVIOUSLY IRRADIATED MEDULLOBLASTOMA
Authors: Ekaterina Salnikova, Irina Vilesova, Artur Merishavyan, Alexander Druy, Ludmila Yasko, Andrey Sysoev, Alexey Nechesnyuk, Irina Borodina, Alexander Karachunsky, Galina Novichkova, Ludmila Papusha
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/OBJECTIVES Relapse of medulloblastoma (MB) is highly lethal in previously irradiated patients. As one of therapeutic options for recurrence MB, high-dose chemotherapy with stem cell rescue (HDSCR) is suggested. The aim of our work was to evaluate the effectiveness of this therapy. DESIGN/METHODS We retrospectively analyzed the data of 8 pts with previously irradiated relapse MB using HDSCR. Initially, M0-stage was verified in 4 cases. Histological diagnoses were desmoplastic (2 pts), classic (2 pts), anaplastic (2 pts) and MB NOS (2 pts). Molecular genetic analyses was performed in 6 cases: Group 3 was verified in 2 cases (1-classic, 1-anaplastic), Group 4 – in 3 cases (1-classic, 1-anaplastic, 1-desmoplastic). Time to first PD was from 15 to 86 months (median=29,4 months). Local relapse was revealed in 1 pt, metastatic – in 5 pts, mixed – in 2 pts. RESULTS All pts were treated according HIT-REZ 2005 (3–5 cycles without/with intraventricular etoposide), with CR achieved in 3 pts and PR in 5 pts. HDCT regimens consisted of carboplatin, etoposide, thiotepa and temozolomide. 2 pts received re-irradiation – focal RT (1) and CSI (1). 7/8 patients died, 1 pt alive with PD. Time from HDCT to death was 5–15 months (median=9,6 months). CONCLUSIONS HDSCR for recurrent previously irradiated MB is ineffective. Use of other methods should be considered in these cases.
EXTH-62. PRECLINICAL EFFICACY OF THE IMIPRIDONE ONC-206 AGAINST MEDULLOBLASTOMA
Authors: Tobey MacDonald, Anshu Malhotra, Jingbo Liu, Hongying Zhang, Matthew Schneiderjan, Jose Velazquez Vega, Varun Prabhu, Joshua Allen
Journal: Neuro-Oncology (2020)

Abstract Treatment for medulloblastoma (MB) is typically ineffective for MYC amplified or metastatic SHH, Group 3 and 4 subgroups. Promising preclinical and clinical results have been obtained for adult and pediatric malignant glioma treated with ONC-201, a selective antagonist of DRD2, a G-protein coupled receptor that regulates prosurvival pathways. Herein, we report the activity of ONC-201 and ONC-206, which has increased non-competitive antagonism of DRD2, against MB. We treated three different MB cell types representative of SHH- and Group 3-like cells, with varied levels of DRD2 expression, and consistently observed increased cell death in a dose-dependent manner at lower doses of ONC-206 compared to ONC-201. We also evaluated ClpP as an additional drug target in MB. ClpP is a mitochondrial protease that has been shown to directly bind and be activated by ONC 201, and is highly expressed at the protein level across pediatric MB, malignant glioma and ATRT, but not normal brain. We observed that similar to ONC-201, ONC-206 treatment of MB cells induces the restoration of mitochondrial membrane potential to the non-proliferative state, degradation of the mitochondrial substrate SDHB, reduction in survivin and elevation in ATF4 (integrated stress response). Importantly, ONC-206 treatment induced significant cell death of patient-derived SHH, WNT, and Group 3 tumors ex vivo and Group 4 cells in vitro, while having no observable toxicity in normal brain. ONC-206 treatment of a transgenic mouse model of Shh MB in vivo significantly reduces tumor growth and doubles survival time in a dose-dependent manner following 2 weeks of therapy. Additional in vivo data will be reported in preparation for a planned Phase I study of ONC-206 in children with malignant brain tumors.
ATRT-22. HIGH-THROUGHPUT DRUG SCREENING OF FDA-APPROVED CANCER DRUGS REVEALS POTENTIAL THERAPEUTIC APPROACHES FOR ATYPICAL TERATOID RHABDOID TUMOUR
Authors: Wai Chin Chong, Nataliya Zhukova, Paul Wood, Peter A Downie, Jason E Cain
Journal: Neuro-Oncology (2020)

Abstract Atypical teratoid/rhabdoid tumors (ATRT), are the most common brain tumor in children under the age of 1 year with an overall survival of ~17%. Like extracranial rhabdoid tumors, ATRT is exclusively characterized by bi-allelic loss of SMARCB1, a critical subunit of the SWI/SNF chromatin remodeling complex, implicating epigenetic deregulation in the pathogenesis of disease. We have previously shown the ability of the histone deacetylase inhibitor, panobinostat, to mimic SMARCB1-mediated SWI/SNF functions in extracranial rhabdoid tumors to inhibit tumor growth by driving multi-lineage differentiation in vitro and in vivo. Whether this also applies to ATRT is unknown. Using a panel of human-derived ATRT cell lines, representing defined molecular subgroups, we have shown that prolonged treatment with panobinostat at nanomolar concentrations results in markedly reduced clonogenicity, and increased senescence, preceded by increased H3K27 acetylation, decreased H3K27 trimethylation and EZH2 expression. To determine potentially synergistic therapies, we performed high-throughput drug screening of 622 compounds already in advanced clinical trials or FDA-approved for other indications, across our panel of ATRT models and identified 30 common compounds, which decrease cell viability by &amp;gt;50%, with no effect on neural stem cell controls and 12 compounds which demonstrated subgroup specificity, highlighting the necessity to consider therapies in the molecular context. In addition to HDACi, consistent with our panobinostat in vitro findings, inhibitors of CDK, survivin and PI3K were the top hits. In vitro and in vivo validation of these compounds alone, and in combination with panobinostat is ongoing.
Serum Phosphate Concentrations: A Novel Pre-Clinical Biomarker for Cardiovascular Calcification⁎⁎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: Nalini M. Rajamannan
Journal: Journal of the American College of Cardiology (2011)
Suppression of IgE-mediated anaphylaxis and food allergy with monovalent anti-FcεRIα mAbs
Authors: Marat V. Khodoun, Suzanne C. Morris, Wen-Hai Shao, Crystal Potter, Elizabeth Angerman, Artem Kiselev, Alexander E. Yarawsky, Andrew B. Herr, Katja Klausz, Anna Otte, Matthias Peipp, Fred D. Finkelman
Journal: Journal of Allergy and Clinical Immunology (2020)
EPCO-35. SINGLE-CELL RNA-SEQ OF PEDIATRIC EPENDYMOMA REVEALS PROGNOSTIC IMPACT OF IMPAIRED NEURONAL-GLIAL FATE SPECIFICATION
Authors: Bernhard Englinger, Johannes Gojo, Li Jiang, Jens M Hübner, McKenzie Shaw, Olivia Hack, Ilon Liu, Sibylle Madlener, Dominik Kirchhofer, Jason Pyrdol, Volker Hovestadt, Emanuele Mazzola, Nathan Mathewson, Maria Trissal, Daniela Lötsch, Christian Dorfer, Christine Haberler, Angela Halfmann, Lisa Mayr, Andreas Peyrl, Rene Geyeregger, Benjamin Schwalm, Monica Mauermann, Kristian Pajtler, Till Milde, Marni Shore, Jack Geduldig, Kristine Pelton, Thomas Czech, Orr Ashenberg, Kai Wucherpfennig, Orit Rozenblatt-Rosen, Sanda Alexandrescu, Keith Ligon, Stefan Pfister, Aviv Regev, Irene Slavc, Walter Berger, Mario Suva, Marcel Kool, Mariella Filbin
Journal: Neuro-Oncology (2020)

Abstract Ependymoma represents a heterogeneous disease affecting the entire neuraxis. Extensive molecular profiling efforts have identified molecular ependymoma subgroups based on DNA methylation. However, the intratumoral heterogeneity and developmental origins of these groups are only partially understood, and effective treatments are still lacking for about 50% of patients with high-risk tumors. We interrogated the cellular architecture of ependymoma using single cell/single nucleus RNA-sequencing to analyze 24 tumor specimens across major molecular subgroups and anatomic locations. We additionally analyzed ten patient-derived ependymoma cell models and two patient-derived xenografts (PDXs). Interestingly, we identified an analogous cellular hierarchy across all ependymoma groups, originating from undifferentiated neural stem cell-like populations towards different degrees of impaired differentiation states comprising neuronal precursor-like, astro-glial-like, and ependymal-like tumor cells. While prognostically favorable ependymoma groups predominantly harbored differentiated cell populations, aggressive groups were enriched for undifferentiated subpopulations. Projection of transcriptomic signatures onto an independent bulk RNA-seq cohort stratified patient survival even within known molecular groups, thus refining the prognostic power of DNA methylation-based profiling. Furthermore, we identified novel potentially druggable targets such as IGF- and FGF-signaling within poorly prognostic transcriptional programs. Ependymoma-derived cell models/PDXs widely recapitulated the transcriptional programs identified within fresh tumors and are leveraged to validate identified target genes in functional follow-up analyses. Taken together, our analyses reveal a developmental hierarchy and transcriptomic context underlying the biologically and clinically distinct behavior of ependymoma groups. The newly characterized cellular states and underlying regulatory networks could serve as basis for future therapeutic target identification and reveal biomarkers for clinical trials.
IMMU-49. PREDICTING PATIENT-SPECIFIC ANTIGENS FOR MEDULLOBLASTOMA IMMUNOTHERAPY
Authors: Kyle Dyson, Changlin Yang, Vrunda Trivedi, Tyler Wildes, Adam Grippin, Duane Mitchell
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Identification of tumor rejection antigens remains a major barrier to the development of effective immunotherapeutics and their application to pediatric brain tumors. To identify candidate antigen targets for medulloblastoma adoptive cellular therapy, we performed a comprehensive immunogenomic analysis of medulloblastoma transcription profiles and in silico antigen prediction across a broad array of antigen classes. We hypothesized that medulloblastomas are immunologically heterogeneous and express genes with limited normal tissue expression that may serve as targets for immunotherapy. METHODS Immunologic heterogeneity was assessed using several published algorithms and approaches implemented within the R programming language. Patient-specific HLA haplotypes were called via customized Optitype and Phlat algorithms. Patient-specific tumor associated antigens (TAA) were selected only if expressed &amp;gt;1 transcript per million (TPM) in tumor and the standardized expression across a human tissue database was below 1 TPM. Patient-specific HLA and TAA sequences were extracted from RNA-seq data for prediction with eight MHC class I and four MHC class II affinity algorithms. Only expressed mutations and personalized TAAs were used for antigenic epitope predictions. All epitopes were screened against a human reference proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. Public mass-spec data was also screened for protein-level antigen expression. RESULTS Although absolute immune cell content is predicted to be low, immune gene-signature analysis revealed subgroup-specific differences. Antigen prediction analysis revealed most patients express few candidate neoantigen targets passing all filtering criteria. Importantly, cancer testis antigens as well as previously unappreciated neurodevelopmental antigens were found expressed across all medulloblastoma subgroups and most patients. Protein level antigen expression was confirmed for some predicted TAAs. CONCLUSION Medulloblastomas are immunologically cold yet subgroups have distinct immune cell gene-signatures. Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for development of medulloblastoma cellular therapies.