tbuckley/cabot-search huggingface dataset:
TAMI-45. PHENOGENOMIC CHARACTERIZATION OF IMMUNOMODULATORY PURINERGIC SIGNALING IN GLIOBLASTOMA
Authors: Shannon Coy, Rumana Rashid, Sylwia Stopka, Jia-Ren Lin, Philipp Euskirchen, Jaeho Hwang, Prasidda Khadka, Pratiti Bandopadhayay, Patrick Wen, Peter Sorger, Nathalie Y R Agar, Keith Ligon, Mehdi Touat, Sandro Santagata
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Purinergic signaling plays critical roles in the regulation of tumor growth and anti-tumor immunity via autocrine/paracrine binding of metabolites to receptors on neoplastic and non-neoplastic populations. Extracellular purine concentrations are mediated by the ectonucleotidase enzymes CD39 and CD73, which catabolize ATP to adenosine. Within tumors such as glioblastoma, neoplastic, immune, and stromal cells expressing these enzymes may co-localize to generate immunosuppressive adenosine-rich environments. However, the composition, architecture, and phenotypic properties of these tumor ecosystems and their relationship to tumor genotype are poorly characterized. METHODS We quantified CD73 expression by immunohistochemistry in a cohort of CNS tumors [meningiomas(n=222), gliomas(n=244), ependymomas(n=44), medulloblastomas(n=24), and craniopharyngiomas(n=38)]. We used publicly-available single-cell RNA-seq data and 36-marker multiplexed tissue imaging (t-CyCIF) of 139 clinically and genomically annotated glioblastoma resections to characterize CD39 and CD73-expressing populations, define the immune architecture and tumor cell-states at single cell resolution, and identify markers of clinical outcome. We used mass spectrometry imaging (MALDI-MSI) to generate spatially-resolved quantification of purine metabolite levels in glioblastoma resections (n=10). RESULTS CD73 exhibited strong expression in a subset of gliomas and meningiomas but was typically not expressed in ependymomas or medulloblastomas. CD73 expression correlated with poor progression-free-survival in IDH-wildtype glioblastoma (p=0.04). scRNA-seq and t-CyCIF in glioblastoma showed CD73 expression in tumor cells, and CD39 expression in macrophages and endothelial cells. MALDI-MSI showed significantly greater adenosine concentrations (3.5-fold;p=0.04) in glioblastomas with high CD73 expression. scRNA-seq showed direct correlations between stem-like mRNA expression, proliferation, and CD73 expression in DIPG. CD73 expression significantly correlated with EGFR amplification, interferon signaling, and PD-L1 expression in glioblastoma. CONCLUSIONS Phenogenomic analysis of purinergic immunomodulatory signaling revealed significant interplay between CD73 activity and genotype, adenosine concentration, differentiation-state, clinical outcome, and possible interaction between CD39-positive macrophages and CD73-positive neoplastic cells. Anti-CD73 therapy may provide therapeutic benefits in glioblastoma by blunting immunosuppressive and oncogenic adenosine signaling.
Microglial Gi-dependent dynamics regulate brain network hyperexcitability
Authors: Mario Merlini, Victoria A. Rafalski, Keran Ma, Keun-Young Kim, Eric A. Bushong, Pamela E. Rios Coronado, Zhaoqi Yan, Andrew S. Mendiola, Elif G. Sozmen, Jae Kyu Ryu, Matthias G. Haberl, Matthew Madany, Daniel Naranjo Sampson, Mark A. Petersen, Sophia Bardehle, Reshmi Tognatta, Terry Dean, Rosa Meza Acevedo, Belinda Cabriga, Reuben Thomas, Shaun R. Coughlin, Mark H. Ellisman, Jorge J. Palop, Katerina Akassoglou
Journal: Nature Neuroscience (2020)
ROBERT BARANY (1876-1936)— INVESTIGATOR OF LABYRINTHINE FUNCTION
Journal: JAMA (1965)

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American Society of Clinical Oncology Road to Recovery Report: Learning From the COVID-19 Experience to Improve Clinical Research and Cancer Care
Authors: Nathan A. Pennell, Melissa Dillmon, Laura A. Levit, E. Allyn Moushey, Ajjai S. Alva, Sibel Blau, Timothy L. Cannon, Natalie R. Dickson, Maximilian Diehn, Mithat Gonen, Maria Magdalena Gonzalez, Jack O. Hensold, Leslie J. Hinyard, Tari King, Stacie C. Lindsey, Allison Magnuson, Jonathan Marron, Barbara L. McAneny, Theresa M. McDonnell, Kathryn Finch Mileham, Shelley Fuld Nasso, Grzegorz S. Nowakowski, Kurt R. Oettel, Manali I. Patel, Debra A. Patt, Jane Perlmutter, Todd A. Pickard, Gladys Rodriguez, Abby R. Rosenberg, Barry Russo, Connie Szczepanek, Cardinale B. Smith, Piyush Srivastava, Eleonora Teplinsky, Ramya Thota, Tiffany A. Traina, Robin Zon, Brian Bourbeau, Suanna S. Bruinooge, Shelagh Foster, Stephen Grubbs, Karen Hagerty, Patricia Hurley, Deborah Kamin, Jonathan Phillips, Caroline Schenkel, Richard L. Schilsky, Howard A. Burris
Journal: Journal of Clinical Oncology (2020)

This report presents the American Society of Clinical Oncology's (ASCO's) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.
DIPG-57. TRANSCRIPTOMIC AND PROTEOMIC ANALYSES OF DIPG RESPONSE TO ONC201
Authors: Sreepradha Sridharan, Arif Harmanci, Ajay Sharma, Yanlai Lai, Bridget Kennis, Tara Dobson, Jyothishmathi Swaminathan, Amanda Haltom, Soumen Khatua, Rohinton Tarapore, Joshua Allen, Donghang Cheng, Wafik Zaky, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. Current standard of care has shown no improvements in survival. Here, we report our study of ONC201, a first-in-class small molecule developed by Oncoceutics, Inc., against a panel of DIPG cells in vitro and in mouse orthotopic models. ONC201 inhibits signaling through dopamine receptor D2 (DRD2), a G protein-coupled receptor (GPCR). MTT assays revealed a delayed but more robust response to ONC201, as measured by IC50 values, in DIPGs with histone H3.3-K27M expression compared to cells expressing wildtype (WT) or K27M mutant histone H3.1. Interestingly, transcriptomic profiling identified an association of this response delay with an elevation of genes controlling the cellular unfolded protein response, lysosomal and vacuole organization, and a decline in nucleic acid biosynthetic genes. These cells were also more committed to neuronal and oligodendrocytic lineage specification. By contrast, WT-H3 DIPGs that survived ONC201 treatment were stem-like and exhibited altered expression of genes controlling cell proliferation and apoptosis induction, respectively. Single cell proteomics validated the increase in anti-apoptotic proteins in these cells. Intraperitoneal administration of ONC201 for 7-weeks in mice bearing pontine xenografts of histone H3.1-K27M mutant DIPGs, caused a complete blockade of tumor growth relative to untreated controls. However, identical treatment of animals with forebrain tumors resulted only in a partial reduction in tumor burden, suggesting that the tumor microenvironment may be involved in the differential effect. These data indicate that tumor intrinsic and extrinsic factors may contribute to the response of DIPG tumors to ONC201.
Immunomodulation by targeted anticancer agents
Authors: Giulia Petroni, Aitziber Buqué, Laurence Zitvogel, Guido Kroemer, Lorenzo Galluzzi
Journal: Cancer Cell (2020)

At odds with conventional chemotherapeutics, targeted anticancer agents are designed to inhibit precise molecular alterations that support oncogenesis or tumor progression. Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy. Here, we discuss the main immunomodulatory effects of targeted anticancer agents and explore potential avenues to harness them in support of superior clinical efficacy.
NIMG-16. EXPLORATORY EVALUATION OF Q-SPACE TRAJECTORY IMAGING PARAMETERS AS NOVEL IMAGING BIOMARKERS FOR GLIOMAS
Authors: Parikshit Juvekar, Filip Szczepankiewicz, Thomas Noh, Carl-Fredrik Westin, Alexandra Golby
Journal: Neuro-Oncology (2020)

Abstract Neuroimaging offers a non-invasive means to probe tumor tissue in order to inform decision making at all phases of brain tumor treatment. Diffusion MRI is particularly sensitive to tumor tissue microstructure, with greater heterogeneity being reflected as a larger diffusional kurtosis. Q-Space Trajectory Imaging (QTI) uses tensor-valued diffusion encoding (encoding along multiple directions per shot) to disentangle Isotropic Mean Kurtosis (MKi) from Anisotropic Mean Kurtosis (MKa), which are otherwise conflated in the Total Mean Kurtosis (MKt). To test whether disentangling MKi and MKa facilitates a more specific probe of tumor tissue heterogeneity and malignancy, we investigated if QTI parameters could distinguish low- from high-grade gliomas and enhancing from non-enhancing regions using pre-operative QTI imaging of 13 W.H.O. grade I-II and 18 grade III-IV glioma patients. We also analyzed these features separately for de novo and recurrent tumors. Regions of Interest (ROIs) were drawn on QTI maps, with support from T1 and T2-weighted images, for enhancing region, non-enhancing region, necrotic cavity, cyst, edema and resection cavity. ROC was used to gauge QTI parameter performance in classifying tumor characteristics. MKi was found to be the strongest predictor of tumor grade (AUC = 0.74, p = 0.019). MKi and MKt separated de novo from recurrent tumors (AUC = 0.80 and 0.76, p &amp;lt; 0.05). MKt separated enhancing regions from non-enhancing regions with an AUC of 0.88 in all tumors and 0.97 in de novo tumors. Our preliminary results highlight that tensor-valued diffusion MRI and QTI analysis have the potential to non-invasively characterize tumor grade. Further, MKt accurately differentiated enhancing from non-enhancing tumors and could potentially substitute for gadolinium injection in some situations thereby decreasing risk, time, and cost. Our ongoing studies in larger groups aim to further correlate molecular tumor markers (eg. IDH1 status) with these diffusion parameters.
RONC-02. MEASURING THE EFFECT OF CLINICALLY-RELEVANT RADIOTHERAPY PROTOCOLS ON THE JUVENILE MOUSE BRAIN
Authors: Jessica Buck, Kale Somers, Jacqueline Whitehouse, Meegan Howlett, Hilary Hii, Brooke Strowger, Martin Ebert, Andrew Mehnert, Nick Gottardo, Raelene Endersby
Journal: Neuro-Oncology (2020)

Abstract Treatment for medulloblastoma involves craniospinal irradiation which is associated with devastating late effects. Clinical trials that simply reduce radiotherapy dosage have resulted in inferior survival rates, whereas new chemo/radiotherapy combinations that improve survival have been identified using preclinical models. However, the potential late effects of novel treatments are currently understudied and the assessment of radiation-induced late effects in mice remains challenging. Here, we aimed to measure the effect of multifractionated radiotherapy on the juvenile mouse brain as a baseline measure for future studies. NOD/Rag1-/- mice received either 8Gy whole-brain radiotherapy (WBRT) using an X-RAD SmART preclinical platform, 18Gy fractionated WBRT (9x2Gy doses), single, or multiple sham treatments beginning at postnatal day (P)16. Mice were aged to adulthood (&amp;gt;P63), then high resolution anatomical brain scans were obtained on a Bruker 9.4T MRI to measure the effects of WBRT on whole brain and specific regional area volumes. A single 8Gy dose (n=10) markedly reduced brain volume by 8.5% compared to single-sham controls (n=11, p&amp;lt;0.0001), whereas fractionated 18Gy treatment (n=7) did not cause significant differences in brain volume compared to multi-sham controls (n=4, p&amp;gt;0.99). Current analyses are focused on measuring treatment effects on specific areas of the brain, as well as other anatomical differences using a range of MRI techniques. These results will serve as a valuable tool to measure potential treatment-associated effects caused by novel chemo/radiotherapy combinations on the developing brain. This will enable future studies to assess the potential safety of novel treatment to inform clinical decision making.
CTNI-16. FEASIBILITY PILOT STUDY OF OKN-007 IN COMBINATION WITH ADJUVANT TEMOZOLOMIDE CHEMORADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: James Battiste, Sarah Sung, Deborah Wright, Chad Glenn, Ozer Algan, April Teague, Yan Zhao, Andrew Cohoon, Hyun Sook Kim, Rheal Towner
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Temozolomide (TMZ) is the standard of care chemotherapy agent for glioblastoma. Unfortunately, intrinsic or acquired resistance eventually renders TMZ ineffective. The novel anti-cancer agent OKN-007 plus TMZ increased survival in glioma-bearing mice compared to TMZ alone. Furthermore, OKN-007 increased TMZ sensitivity in both TMZ-sensitive and TMZ-resistant cell lines. Therefore, we initiated a clinical trial (NCT03587038) of OKN-007 in combination with TMZ and radiation therapy (RT). Here we report the safety and tolerability findings of this trial in-progress. METHODS Adults with newly-diagnosed and resected GBM are eligible. OKN-007 is administered by IV at 60 mg/kg. There are three treatment phases: Concomitant, Pre-Maintenance, and Maintenance. In the Concomitant Phase, patients receive OKN-007 three times per week (Cohort 1) or five times per week (Cohort 2); all patients receive TMZ at 75 mg/m2 daily and RT at 60 Gy over 30 fractions. In the 28-day Pre-Maintenance Phase, all patients receive OKN-007 thrice weekly. In the Maintenance Phase (MP), comprising up to eighteen 28-day cycles, TMZ is dosed at 150–200 mg/m2 on days 1–5 of each cycle for six cycles. OKN-007 is administered thrice weekly for six cycles, then twice weekly for three cycles, then once weekly for nine cycles. An expansion cohort of up to 25 patients will use the highest tolerated dosing protocol. RESULTS To date, five patients have been enrolled. Three patients in Cohort 1 and one in Cohort 2 advanced to the MP, and no dose-limiting toxicities (DLTs) occurred. One patient in Cohort 2 was removed due to a DLT (grade 3 neutropenic fever). CONCLUSIONS The treatment plan in Cohort 1 appears safe and well-tolerated. Recruitment for Cohort 2 is ongoing and will be expanded to further evaluate safety. Once the outcome of Cohort 2 is known, the regimen for the expansion cohort will be determined.
Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications
Authors: Anita Jeyam, Helen Colhoun, Stuart McGurnaghan, Luke Blackbourn, Timothy J. McDonald, Colin N.A. Palmer, John A. McKnight, Mark W.J. Strachan, Alan W. Patrick, John Chalmers, Robert S. Lindsay, John R. Petrie, Sandeep Thekkepat, Andrew Collier, Sandra MacRury, Paul M. McKeigue
Journal: Diabetes Care (2020)

OBJECTIVE To quantify the relationship of residual C-peptide secretion to glycemic outcomes and microvascular complications in type 1 diabetes. RESEARCH DESIGN AND METHODS C-peptide was measured in an untimed blood sample in the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) cohort of 6,076 people with type 1 diabetes monitored for an average of 5.2 years. RESULTS In regression models adjusted for age at onset and duration, effect sizes for C-peptide ≥200 vs. &amp;lt;5 pmol/L were as follows: insulin dose at baseline, 9% lower (P = 2 × 10−17); HbA1c during follow-up, 4.9 mmol/mol lower (P = 3 × 10−13); hazard ratio for hospital admission for diabetic ketoacidosis during follow-up, 0.44 (P = 0.0001); odds ratio for incident retinopathy, 0.51 (P = 0.0003). Effects on the risk of serious hypoglycemic episodes were detectable at lower levels of C-peptide, and the form of the relationship was continuous down to the limit of detection (3 pmol/L). In regression models contrasting C-peptide 30 to &amp;lt;200 pmol/L with &amp;lt;5 pmol/L, the odds ratio for self-report of at least one serious hypoglycemic episode in the last year was 0.56 (P = 6 × 10−8), and the hazard ratio for hospital admission for hypoglycemia during follow-up was 0.52 (P = 0.03). CONCLUSIONS These results in a large representative cohort suggest that even minimal residual C-peptide secretion could have clinical benefit in type 1 diabetes, in contrast to a follow-up study of the Diabetes Control and Complications Trial (DCCT) intensively treated cohort where an effect on hypoglycemia was seen only at C-peptide levels ≥130 pmol/L. This has obvious implications for the design and evaluation of trials of interventions to preserve or restore pancreatic islet function in type 1 diabetes.
CTIM-09. DOUBLE-BLINDED, PLACEBO CONTROLLED PHASE 2 STUDY OF ERC1671 IN RECURRENT GLIOBLASTOMA: VACCINE OVERALL SURVIVAL IN BEVACIZUMAB NAIVE AND BEVACIZUMAB RESISTANT PATIENTS
Authors: Daniela Bota, Thomas Taylor, Xiao-Tang Kong, Beverly Fu, Frank Hsu, Ankie Strik, Virgil Schijns, Apostolos Stathopoulos
Journal: Neuro-Oncology (2020)

Abstract ERC1671 is an allogeneic/autologous therapeutic vaccine – composed of whole, inactivated tumor cells mixed with tumor- cell lysates. The hypothesized action of ERC1671 is to potentiate the patients’ immune system against the tumor. Goals of this ongoing, phase 2 study are to determine the safety and effectiveness (overall survival) of ERC1671 in combination with GM-CSF and cyclophosphamide as an add-on treatment to bevacizumab at the time of GBM recurrence. To date 22 recurrent bevacizumab-naïve rGBM patients have been randomized to ERC1671/GM-CSF/Cyclophosphamide + Bevacizumab or Placebo + Bevacizumab. Median age is 56.5 (33–74), 7 patients (32%) are female, and average KPS is 82.3 (70–100). Of the 22, two discontinued before completing one cycle of therapy and two remain on blinded treatment. Currently 18 patients are unblinded due to further progression: 8 were on vaccine and 10 on placebo. Five of those on placebo crossed to vaccine at progression. All but one of the 18 are now deceased. Median overall survival of unblinded patients randomized to ERC1671 + Bevacizumab (n = 8) is 264.5 days from the start of study treatment, compared to 182 days for those randomized to placebo + Bevacizumab who did not cross over (n = 5). Median overall survival of unblinded patients on vaccine at randomization or crossover is 328 days after first study treatment (n = 13). While sparse, the data to date suggest pre-treatment and maximal CD4+T lymphocyte count in the peripheral blood correlate with OS more strongly in the ERC1671 group than in the placebo group. First clinical results for toxicity show no difference in the distribution of AEs between the Vaccine and Placebo groups, with no Gr4/Gr5 AEs in either group. This phase 2 randomized, double-blinded study is ongoing, with the addition of one more site.
Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis
Authors: Anthony D So, Joshua Woo
Journal: BMJ (2020)

To analyze the premarket purchase commitments for coronavirus disease 2019 (covid-19) vaccines from leading manufacturers to recipient countries. Cross sectional analysis. World Health Organization's draft landscape of covid-19 candidate vaccines, along with company disclosures to the US Securities and Exchange Commission, company and foundation press releases, government press releases, and media reports. Premarket purchase commitments for covid-19 vaccines, publicly announced by 15 November 2020. Premarket purchase commitments for covid-19 vaccine candidates and price per course, vaccine platform, and stage of research and development, as well as procurement agent and recipient country. As of 15 November 2020, several countries have made premarket purchase commitments totaling 7.48 billion doses, or 3.76 billion courses, of covid-19 vaccines from 13 vaccine manufacturers. Just over half (51%) of these doses will go to high income countries, which represent 14% of the world's population. The US has reserved 800 million doses but accounts for a fifth of all covid-19 cases globally (11.02 million cases), whereas Japan, Australia, and Canada have collectively reserved more than one billion doses but do not account for even 1% of current global covid-19 cases globally (0.45 million cases). If these vaccine candidates were all successfully scaled, the total projected manufacturing capacity would be 5.96 billion courses by the end of 2021. Up to 40% (or 2.34 billion) of vaccine courses from these manufacturers might potentially remain for low and middle income countries-less if high income countries exercise scale-up options and more if high income countries share what they have procured. Prices for these vaccines vary by more than 10-fold, from $6.00 (£4.50; €4.90) per course to as high as $74 per course. With broad country participation apart from the US and Russia, the COVAX Facility-the vaccines pillar of the World Health Organization's Access to COVID-19 Tools (ACT) Accelerator-has secured at least 500 million doses, or 250 million courses, and financing for half of the targeted two billion doses by the end of 2021 in efforts to support globally coordinated access to covid-19 vaccines. This study provides an overview of how high income countries have secured future supplies of covid-19 vaccines but that access for the rest of the world is uncertain. Governments and manufacturers might provide much needed assurances for equitable allocation of covid-19 vaccines through greater transparency and accountability over these arrangements.