tbuckley/cabot-search huggingface dataset:
IMMU-32. RNA-NANOPARTICLE VACCINES MEDIATE T CELL TRAFFICKING NECESSARY FOR BBB PASSAGE AND ANTI-GLIOMA IMMUNE RESPONSE
Authors: Hector Mendez-Gomez, Brandon Wummer, Adam Grippin, Frances Weidert, Jianping Huang, Loic Deleyrolle, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The blood-brain barrier (BBB) remains a potent obstacle for development of new therapies against glioblastoma (GBM). While activated T cells can cross the BBB, immunotherapy has yet to be fully unlocked for malignant brain tumors due their heterogeneity and immunosuppressive microenvironments. To overcome these challenges, our group has developed a novel treatment platform, which leverages the use of a clinically translatable nanoparticles (NPs) combined with personalized tumor derived mRNA to peripherally activate T cells against a heterogenous source of tumor antigens and reprogram the intratumoral milieu into an immune activated state. OBJECTIVE We sought to assess if RNA-NPs could activate systemic/intratumoral dendritic cells (DCs) and mediate a peripheral T cell response that could penetrate the GBM microenvironment. RESULTS We uncovered that RNA-NPs elicit potent innate immunomodulating effects through release of interferon-α (IFN-α) from plasmacytoid DCs (pDCs). After only a single RNA-NP vaccine, the bulk of systemic and intratumoral DCs in mice display an activated phenotype; DCs, harvested from intracranial tumors, elicit expansion of antigen specific T cell immunity. Tumor-specific RNA-NPs elicited enhanced survival outcomes in immunocompetent animals bearing NF-1/p53 mutant gliomas with increased intratumoral memory CD8+T-cells. Unlike immune checkpoint blockade (anti-PD-L1 mAbs), we found that RNA-NPs increase LFA-1 on peripheral CD8 splenocytes, which is necessary for activated T cell passage across the BBB. RNA-NPs also increased CCR2 on peripheral CD8 cells, which was dependent on IFN-α/β, as the percentage of CCR2+CD8+ splenocytes and anti-tumor activity (mediated by RNA-NPs) was abrogated in animals receiving concomitant type I IFN receptor (IFNAR1) mAbs. CONCLUSION Since LFA-1 is important for T cell trafficking across the BBB and CCR2 may promote chemotaxis to the brain (as GBMs are known to secrete CCL2), RNA-NPs may offer a new treatment modality and immunologic mechanism for unlocking peripheral T cell immunity against malignant gliomas.
Clinical and Prognostic Impact of (11;14)(q13;q32) Translocation on Patients with Multiple Myeloma
Authors: Daisuke Miura, Kentaro Narita, Ayumi Kuzume, Rikako Tabata, Toshiki Terao, Takafumi Tsushima, Hiroki Kobayashi, Yoshiaki Abe, Akihiro Kitadate, Masami Takeuchi, Kosei Matsue
Journal: Blood (2019)
RDNA-13. DOSE RESPONSE CURVE FOR RADIATION-INDUCED HYPERSOMNOLENCE (RIH) IN A MOUSE MODEL OF CRANIAL RADIATION: BEHAVIORAL ANALYSIS OF SLEEP AND ACTIVITY
Authors: Demarrius Young, Dee Dee Smart, Amanda King, Mark Gilbert, Terri Armstrong, Dorela Shuboni-Mulligan
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Radiation therapy is the standard of care for both primary and secondary brain tumors. The majority of patients experience radiation induced hypersomnia (RIH) to varying extents which may impact life quality and treatment tolerance. Previously, we demonstrated that risk is enhanced by presence of select clock gene polymorphisms. The purpose of this study is to establish a mouse model of RIH to test dose effects of cranial irradiation on behavioral sleep and activity prior to introducing tumor in transgenic mice. METHODS Twenty-four non-tumor bearing C57BL/6 mice received whole brain radiation at one of 4 doses (sham, 2Gy, 5Gy, and 15Gy) using a single fraction. Behavior, total activity (distance) and sleep quantity (seconds) were monitored using Phenotyper cages and Ethovision Software with data collected at baseline (10 days) and post-radiation (11 days); percentage of activity was calculated as post-radiation/baseline activity. Blood and tissue samples were collected. RESULTS Baseline activity was not significantly different between groups (F(3.23) = 0.649, p=0.593). Shams and 2Gy mice were not affected by the procedure and activity levels were unchanged, 99.76±1.3% and 103.3±3.5%, respectively. The higher doses, 5Gy and 15Gy, had suppression of general activity compared to baseline with 90.8±2.7% and 88.9±1.3%, respectively. Between the two groups, suppression of activity started after 2 days in 15Gy and 5 days in 5Gy mice. Across three days (8–10), 5Gy and 15Gy (19,872±577sec) had more sleep during their active phase (t=2.27, p=0.03) than sham or 2Gy (17,618±803sec). CONCLUSION Activity and sleep are affected by cranial irradiation in our RIH mouse model in dose dependent manner. This model closely resembles the effects seen in patients and provides a critical tool for interrogating the physiological drivers of RIH. In future studies, we will examine other behaviors and the association between circadian gene variants and RIH susceptibility as previously reported in patients.
CBMT-20. SINGLE-CELL TRANSCRIPTOMICS RESOLVES CELLULAR HETEROGENEITY AND ONCOGENIC NETWORKS DURING MALIGNANT TRANSFORMATION OF PERIPHERAL NERVE SHEATH TUMORS
Authors: Lai Man Natalie Wu, Feng Zhang, Weidong Tian, Richard Lu
Journal: Neuro-Oncology (2019)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-derived sarcomas with strong metastatic proclivity and resistance to radiation and chemotherapy. Molecular events driving SC-to-MPNST transformation are incompletely understood. MPNST are heterogeneous tumors with a distinct microenvironment that contributes to the establishment of a tumor niche. Cancer behaviors including initiation, progression, metastasis and relapse cannot be fully defined by genetic mutations alone, but are critically dependent on intercellular communication between tumor cells and the microenvironment. However, currently, a comprehensive understanding of tumor cell lineage evolution, heterogeneity and cell-cell communication network in MPNST is lacking. A better understanding of cellular heterogeneity and tumor-initiating cells during tumorigenesis at a single-cell level will facilitate identifying molecular and cellular determinants underlying malignant transformation in MPNST. We have established a murine model of aggressive peripheral nerve malignancy with HIPPO-TAZ/YAP activation (Lats1/2-def mice), which provides a unique opportunity for dissecting mechanisms of SC malignant transformation. To identify potential PNST-driven progenitor populations, we compare single-cell transcriptome profiles of Lats1/2-def sciatic nerve tumors during pre-neoplastic and advanced stages. Our data reveal that early sciatic nerve tumors contain primarily mature SCs, whereas full-blown tumors harbor neoplastic SCs composed of different subsets: fast-proliferating, mesenchymal-like and neural crest stem cell-like cells, indicative of a developmental trajectory from differentiated SCs to tumor-like SCs with distinct molecular and transcriptional signatures. Interestingly, transformed SCs exhibit inflammation gene signature, which may suggest cell-autonomous inflammation-driven reprogramming that drives tumorigenesis. To characterize cellular heterogeneity in MPNST-like tumors, we further identify cell-cell communication networks between SC-derived tumor cells and cancer-associated stromal cells within the tumor microenvironment. In summary, our studies using single-cell transcriptomics in clinically relevant mouse models of PNST reveal tumor cellular heterogeneity and the microenvironment niche for driving SC tumorigenesis. It will provide principles for identifying potential targets or treatment strategies to cure MPNST.
IMMU-05. DISRUPTION OF THE CCR2 CHEMOKINE RECEPTOR PATHWAY OVERCOMES THERAPEUTIC RESISTANCE TO PD-1 BLOCKADE IN MALIGNANT GLIOMA
Authors: Joseph Flores-Toro, Defang Luo, James Campbell, Israel Charo, Rajinder Singh, Thomas Schall, Meenal Datta, Rakesh Jain, Duane Mitchell, Jeffrey Harrison
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Large scale clinical trials have failed to determine efficacy of adjuvant PD-1 blockade in recurrent glioblastoma (GBM). However, recent phase 2 clinical trial results demonstrating the potential of neo-adjuvant anti-PD-1 treatment have renewed enthusiasm for the use of immune checkpoint inhibitors (ICIs) in GBM. Additional benefit of ICIs in GBM will likely derive from development of novel therapies directed against immunosuppressive resistance mechanisms. Chemokine receptor 2 (CCR2) expressing tumor infiltrative immune suppressive myeloid cells represent a targetable axis within ICI resistant gliomas. We have established that CCR2 disruption unmasks an effect of anti-PD-1 therapy in ICI resistant murine glioma models. However, the mechanism(s) by which combined inhibition of PD-1 and CCR2 achieves efficacy is unknown. OBJECTIVE Determine the impact of combination anti-PD-1 and CCR2 antagonism on immune cells within anti-PD-1 resistant gliomas. METHODS Immune cell characteristics were determined in CCR2 antagonist (CCX872)/anti-PD-1 treated KR158 or 005 GSC glioma-bearing wild type or CCR2+/rfp/CX3CR1+/gfp reporter mice. RESULTS CCX872 increased median survival (32 vs. 50 days, P=.002) in KR158 tumor-bearing animals and in combination with anti-PD-1 significantly increased durable survival (P=.0005). In 005 GSC glioma-bearing mice, combination therapy also enhanced median survival (30 vs. 49 days, P=.005). CCX872 decreased CD45+/CD11bhi/Ly6Chi MDSCs (40%, P=.038) within gliomas, and increased these cells within bone marrow in both models (74%, P=.020). Three distinct intra-tumoral populations of CCR2+ and CX3CR1+ cells were identified in both glioma models including CCR2+/CX3CR1-/CD45hi/CD11blo, CCR2+/CX3CR1+/CD45hi/CD11bhi/Ly6Chi, and CX3CR1+/CD45lo/CD11bhi/F4/80+/MHCII+, with both CCR2+ populations being reduced by CCX872 treatment. Examination of tumor infiltrating lymphocytes revealed both increased presence and decreased exhaustion (PD-1+/Tim3+) of CD4+ (P=.029) and CD8+ (P=.011) T-cells following CCX872/anti-PD-1 treatment. CONCLUSION CCX872/anti-PD-1 combination therapy is effective in clinically relevant murine glioma models, providing a basis to progress this novel combinatorial treatment to human clinical trials.
Human and Pathogen Derived Ndpks Act As Novel Damps and PAMPs to Drive Leukemia Cell Survival and Progression through Signaling Via the TLR4-Mediated Alternative NLRP3 Inflammasome Pathway
Authors: Sandro Trova, Matthew Fenton, Bhavini Chauhan, Avani Puri, Santosh Lomada, Alexandra Adams, Thomas Wieland, Mark T Drayson, Farhat Latif Khanim, Chistopher M Bunce, Fei Lin
Journal: Blood (2019)
A Prospective Analysis of the Genomic Landscape of Patients with Acute Myeloid Leukemia and Its Impact on Clinical Outcomes - Data from a Tertiary Care Center in India
Authors: Hamza Yusuf Dalal, Sharat Damodar, Vidya Harini Veldore, Coral Miriam K, Shilpa Prabhu, Mukesh Chawla, Bharathram S, Amarnadh Polisetty, Aditi Shah, Shivakumar Komaravelli, Vedam L Ramprasad, Sunil Bhat, Shoba Badiger, Nataraj KS
Journal: Blood (2019)
Health Care Costs Associated with Contemporary Chronic Myelogenous Leukemia (CML) Therapy Compared to Other Hematologic Malignancies (HEM)
Authors: Jennifer J. Wilkes, Gary H. Lyman, David R Doody, Shasank R Chennupati, Laura Becker, Pamela E Morin, Lena E. Winestone, Henry (Joe) Henk, Eric J Chow
Journal: Blood (2019)
Cuts are stopping young adults getting specialist drug treatment, says expert
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A 50% drop in the number of 18-25 year olds presenting for specialist drug treatment over the past decade may be due more to cuts to services than to reduced drug use by young people, an expert on drug policy has argued.

Figures published by Public Health England show that the total number of new treatment presentations by year among people under …
Natural Killer Cell–Derived Vesicular miRNAs: A New Anticancer Approach?
Authors: Muller Fabbri
Journal: Cancer Research (2019)

Abstract Natural killer (NK) cells are cytotoxic lymphocytes targeting virus-infected cells and cancer cells. Specific pro- and antikilling signals modulate the overall ability of NK cells to kill cancer cells, however, several immune-escape mechanisms can be enacted by cancer cells to avoid NK-mediated killing. Recently, increasing evidence has shown that extracellular vesicles (EV) released by NK cells carry proteins and miRNAs able to exert an antitumoral effect, even within a highly immune-suppressive tumor microenvironment. These recent findings suggest a possible use of NK-derived EVs as anticancer agents and propel the development of new strategies to enrich EVs with the most effective anticancer cargo as a promising new anticancer approach.
Maria-I: A Deep-Learning Approach for Accurate Prediction of MHC Class I Tumor Neoantigen Presentation
Authors: Karan R. Kathuria, Binbin Chen, Michael S. Khodadoust, Niclas Olsson, Mark M Davis, Joshua E Elias, Ronald Levy, Russ B. Altman, Arash A. Alizadeh
Journal: Blood (2019)
PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping
Authors: Caspar Da Cunha-Bang, Rudy Agius, Arnon P. Kater, Mark-David Levin, Anders Österborg, Mattias Mattsson, Carsten Utoft Niemann
Journal: Blood (2019)
Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment
Authors: Alice Newey, Beatrice Griffiths, Justine Michaux, Hui Song Pak, Brian J. Stevenson, Andrew Woolston, Maria Semiannikova, Georgia Spain, Louise J. Barber, Nik Matthews, Sheela Rao, David Watkins, Ian Chau, George Coukos, Julien Racle, David Gfeller, Naureen Starling, David Cunningham, Michal Bassani-Sternberg, Marco Gerlinger
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Patient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment. <h3>Methods</h3> Four microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS. <h3>Results</h3> We identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment. <h3>Conclusions</h3> Only 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.
<i>Burkholderia cenocepacia</i>ET12 transmission in adults with cystic fibrosis
Authors: Ana C Blanchard, Lin Tang, Manal Tadros, Matthew Muller, Theodore Spilker, Valerie J Waters, John J LiPuma, Elizabeth Tullis
Journal: Thorax (2019)

This report describes transmission of a Burkholderia cenocepacia ET12 strain (ET12-Bc) at the Toronto Adult Cystic Fibrosis (CF) Centre occurring from 2008 to 2017. Epidemiological and genomic data from 11 patients with CF were evaluated. Isolates were analysed using whole genome sequencing (WGS). Epidemiological investigation and WGS analysis suggested nosocomial transmission, despite enhanced infection control precautions. This was associated with subsequent deaths in 10 patients. ET12-Bc positive patients are no longer cared for on the same unit as ET12-Bc negative patients.
Incorporation of Thiotepa in a Reduced Intensity Conditioning Regimen Leads to Improved Engraftment after Stem Cell Transplant for Patients with Hemophagocytic Lymphohistiocytosis
Authors: Swati Naik, Olive S. Eckstein, Ghadir Sasa, Robert A. Krance, Carl E. Allen, Helen E. Heslop, Caridad A. Martinez
Journal: Blood (2019)
A Combination Therapy with Dendritic Cells, Pomalidomide and Programmed Death-Ligand 1 Blockade Exerts a Potent Antitumor Immunity in a Murine Model of Multiple Myeloma
Authors: Je-Jung Lee, Tan-Huy Chu, Manh-Cuong Vo, Hye-Sung Park, Thangaraj Jaya Lakshmi, Seo-Yeon Ahn, Ga-Young Song, Sung-Hoon Jung, Hyeoung-Joon Kim
Journal: Blood (2019)
Review: In newer CVD primary prevention trials, aspirin vs no aspirin does not reduce MI and increases major bleeding
Authors: Meera Jain, Courtland Childers
Journal: Annals of Internal Medicine (2019)

Source Citation Shah R, Khan B, Latham SB, Khan SA, Rao SV. A meta-analysis of aspirin for the primary prevention of cardiovascular diseases in the context of contemporary preventive strategies. Am J Med. 2019. [Epub ahead of print]. 31153866
Therapeutic Targeting of Monokine Production Is a Promising Strategy to Attenuate Cytokine-Release Syndrome in CAR-T Cell Therapy
Authors: Muneyoshi Futami, Keisuke Suzuki, Satomi Kato, Yoshio Tahara, Yoichi Imai, Takayuki Mimura, Yoshihiro Watanabe, Arinobu Tojo
Journal: Blood (2019)
Impact of Depth of Pretransplant Clinical Response on Outcomes of Acute Myeloid Leukemia Patients in First Complete Remission (AML-CR1) Who Undergo Allogeneic Hematopoietic Cell Transplantation (AlloHCT)
Authors: Mary-Elizabeth M. Percival, Hai-Lin Wang, Mei-Jie Zhang, Elihu H. Estey, Mark Litzow, Partow Kebriaei, Marcos de Lima, Wael Saber, Daniel J. Weisdorf, Brenda M Sandmaier
Journal: Blood (2019)
COMP-09. A CANCER DRUG ATLAS ENABLES PREDICTION OF PARALLEL DRUG VULNERABILITIES OF GLIOBLASTOMA
Authors: Ravi Narayan, Piet Molenaar, Fleur Cornelissen, Tom Wurdinger, Jan Koster, Bart Westerman
Journal: Neuro-Oncology (2019)

Abstract Personalized cancer treatments using synergistic combinations of drugs is attractive but proves to be highly challenging. The combinatorial nature of such problems results in an enormous parameter space that cannot be resolved by empirical research, i.e. testing all combinations for all molecularly defined tumors. In addition, effective drug synergy is hard to predict. Here we present an approach to map data of drug-response encyclopedias and represent these as a drug atlas. This atlas consists of a framework of chemotherapeutic responses that represents a drug vulnerability landscape of cancer. Based on data from the literature we found that many synergistic drug combinations show distinct inter therapy responses and drug sensitivities. We confirmed this by performing a drug combination screen against glioblastoma where we used 270 combination experiments. From the identified dual therapies we were able to predict and validate a triple drug synergy which was validated in vivo. This new and generalizable strategy opens the door to unforeseen personalized multidrug combination approaches.
Sixty seconds on . . . sickies
Authors: Gareth Iacobucci
Journal: BMJ (2019)

That may be so, but new figures from the Office for National Statistics1 (ONS) show that in the UK, sickness absence among normally healthy employees fell to 1.1% last year, the lowest rate since records began and down from 2.2% in 1997.

Indeed. In 2018, the figures show that UK residents took 141.4 million days off work because of sickness or injury—equivalent to 4.4 days per worker. …
RARE-22. CHALLENGES IN MANAGEMENT OF CNS INVOLVEMENT OF CUTANEOUS T-CELL LYMPHOMA
Authors: Ugonma Chukwueke, Albert Kim, Samuel Ng, David Fisher, Robert Stuver, Cecilia Larocca, Abner Louissaint, David Weinstock, Lakshmi Nayak, David Meredith
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Cutaneous T-cell lymphoma (CTCL) is a group of T-cell lymphomas occurring primarily in the skin, without evidence of disease elsewhere. Central nervous system (CNS) involvement of CTCL is extremely rare, with a reported incidence of 5–9%. Due to its infrequency and radiographic appearance which mimics other CNS processes, CNS CTCL may be misdiagnosed. Here, we describe 8 cases of CNS CTCL at a single institution. METHODS The electronic medical records at our institution were queried for cases of CNS involvement by CTCL, between 2004–19. Clinical data, imaging and surgical pathology were reviewed. RESULTS Eight patients were diagnosed with CNS CTCL with median age of 68 and median time to development of CNS disease of 17 months. 1 patient had synchronous presentation of cutaneous and CNS disease identified at autopsy. Seven out of eight patients presented neurologically with behavioral and mental status changes and 1 patient had concurrent intraocular disease. Imaging showed bilateral non-enhancing T2/FLAIR signal changes in three patients; multifocal enhancement was noted in the others. Malignancy, inflammatory processes and infections including progressive multifocal leukoencephalopathy (PML) were often included in the radiographic differential diagnosis. Prior systemic therapies were variable, including palliative radiation, phototherapy, myeloablative chemotherapy followed by allogeneic stem cell transplant and oral methotrexate. 5 of 8 patients had active cutaneous disease at the time of CNS relapse. Six patients received initial treatment for CNS disease with high-dose methotrexate (HD-MTX). Comprehensive genomic analysis revealed recurrent alterations in genes associated with regulatory T-cell differentiation (SOCS1, NOTCH1), tumor suppressors (CDKN2A, PTEN, TP53); one case was hypermutated. CONCLUSIONS CNS involvement of CTCL is rare, occurring more than a year after initial cutaneous disease. Clinical and radiographic findings may be variable, necessitating high clinical suspicion. Most patients respond to HD-MTX. Further molecular analysis is ongoing.
Impact of HFE gene Variants on Iron Overload, Overall Survival and Leukemia-Free Survival in Myelodysplastic Syndromes
Authors: Mathias A. Schneeweiss, Greiner Georg, Susanne Herndlhofer, Julia Schellnegger, Maria-Theresa Krauth, Friedrich Wimazal, Corinna Steinhauser, Renate Thalhammer, Ilse Schwarzinger, Harald Esterbauer, Manuela Födinger, Peter Valent, Wolfgang R. Sperr
Journal: Blood (2019)
Liver Injury in Patients With Cholestatic Liver Disease Treated With Obeticholic Acid
Authors: John E. Eaton, Raj Vuppalanchi, Rajender Reddy, Sanjaya K. Satapathy, Bilal Ali, Patrick S. Kamath
Journal: Hepatology (2019)

Eaton, John E.; Vuppalanchi, Raj; Reddy, Rajender; Satapathy, Sanjaya K.; Ali, Bilal; Kamath, Patrick S. Author Information