tbuckley/cabot-search huggingface dataset:
BIOL-04. DISTAL-LESS/DLX2 HOMEOBOX GENE REGULATION OF CHEMOKINE RECEPTOR CXCR4 - ROLE IN MIGRATION IN FOREBRAIN DEVELOPMENT AND CNS TUMORS
Authors: Sara Japoni, Xiaohua Song, Roger Leng, David Eisenstat
Journal: Neuro-Oncology (2019)

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) have an extremely poor prognosis. Mutations of the genes encoding histone H3K27, especially H3K27M, are highly prevalent. There is reduced expression of the homeobox gene Dlx2 in DIPG with H3K27M mutations. Single cell RNA sequencing suggests that the cell of origin is an oligodendroglial progenitor cell (OPC). DLX2 transcription factors promote GABAergic interneuron differentiation and tangential migration to the neocortex from basal forebrain structures such as the ganglionic eminences (GE) where neural progenitors and OPC both derive. We and others have demonstrated that DLX transcription factors repress OPC differentiation while activating gene networks required for interneuron differentiation and migration. We are exploring the embryonic forebrain and DIPG microenvironment and specifically the role of DLX2 regulation of CXCR4, the receptor for the chemokine CXCL12 essential for interneuron migration. RESULTS: Using chromatin immunoprecipitation of E13.5 mouse GE and our specific polyclonal DLX2 antibody, we isolated seven regions of the Cxcr4 gene promoter occupied by DLX2 in vivo. Subsequently, using electrophoretic mobility shift assays (EMSA), we determined that DLX2 specifically bound to five of these regions containing candidate homeodomain DNA binding sites in vitro. Co-transfection of Dlx2 with a luciferase reporter construct linked to these EMSA (+) Crxcr4 promoter elements demonstrated activation of 4 regions. There was significant loss of Cxcr4 expression in the forebrains of Dlx1/Dlx2 double knockout (DKO) mice. SiRNA knockdown (KD) of Dlx2 significantly reduced Cxcr4 expression in vitro. Cell migration was significantly decreased in the presence of CXCL12 either by Dlx2 KD or by using plerixafor, a CXCR4 signaling inhibitor. CONCLUSIONS: DLX2 binds to the Crxr4 promoter and activates its expression. Pharmacological regulation of CXCR4 signaling may be an important avenue to pursue towards blocking OPC-like DIPG migration and invasion in vivo.
HGG-05. GALLIUM MALTOLATE AS TREATMENT IN PEDIATRIC GLIOMA
Authors: Salvatore Molino, Mona Al-Gizawiy, Jeffrey Knipstein, Kathleen Schmainda, Christopher Chitambar
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas are devastating central nervous system tumors for which effective therapies are lacking. These tumors become rapidly resistant to chemotherapy or radiation therapy. We have shown that adult glioblastomas (U87, D54, and glioblastoma stem cells) have a high requirement for iron to support their growth and viability and that the metallodrug gallium maltolate, GaM, inhibits the growth of glioblastoma in vitro and in vivo in an orthotopic brain tumor rat model. Ga interacts with critical iron-dependent proteins to inhibit mitochondrial function and iron-dependent activity of ribonucleotide reductase. We have initiated investigations to explore the potential antineoplastic activity of GaM in pediatric glioma. Five different pediatric glioma cells lines: 3 glioblastoma (SJ-GBM2, SF188, CHLA-200) and two ATRT (CHLA-266 and CHLA-02) cell lines were incubated for 48 – 96 hours with increasing concentrations of GaM and the effect on cell proliferation was determined by MTT and PE assays. In CHLA-200, SF188, and SJ-GBM2 cells, the IC50 of GaM was 48.4 µM, 73.9 µM and 100 µM, respectively, while in CHLA-266 ATRT cells the IC50 was 16.3 µM after a 96h incubation of cells with GaM. Annexin V staining showed GaM, induces apoptosis in GBM and ATRT cells. Since the majority of glioma patients receive radiation therapy as their first line of treatment, we examined the effects of GaM on cell proliferation after glioma cell lines had been exposed to a single radiation dose of 10 GY. These studies indicate an additive effective of GaM on radiation-induced cell death. Our study is the first to show that GaM inhibits the growth of pediatric gliomas with varying efficacy. Further studies are in progress to investigate differences in iron metabolism among the pediatric glioma cells, drug combinations of GaM with other standard therapeutic agents, and the molecular basis for drug resistance.
Alcohol Rehabilitation Within 30 Days of Hospital Discharge Is Associated With Reduced Readmission, Relapse, and Death in Patients With Alcoholic Hepatitis
Authors: Thoetchai (Bee) Peeraphatdit, Patrick S. Kamath, Victor M. Karpyak, Brian Davis, Vivek Desai, Suthat Liangpunsakul, Arun Sanyal, Naga Chalasani, Vijay H. Shah, Douglas A. Simonetto
Journal: Clinical Gastroenterology and Hepatology (2019)
IMMU-04. DEVELOPMENT OF GPC2-DIRECTED CHIMERIC ANTIGEN RECEPTOR THERAPY FOR PEDIATRIC BRAIN TUMORS WITH IN VITRO TRANSCRIBED mRNA
Authors: Jessica B Foster, Crystal Griffin, Allison Stern, Cameron Brimley, Maria Lane, Samantha Buongervino, Dimiter S Dimitrov, David M Barrett, Adam C Resnick, John M Maris, Kristopher R Bosse
Journal: Neuro-Oncology (2019)

The recent identification of glypican-2 (GPC2) as a cell surface oncoprotein in neuroblastoma, high grade glioma (HGG), and medulloblastoma provides the opportunity for the development of targeted immunotherapy. We hypothesized that chimeric antigen receptor (CAR) T cell therapy directed against GPC2 could be achieved using in vitro transcribed mRNA, allowing for rapid and safe iterative trials to test novel CAR constructs. We created mRNA encoding four different CAR proteins using a GPC2-specific scFv paired with 4-1BB and CD3ζ co-stimulatory domains, with varied heavy and light chain orientation and linker length between chains. After electroporation of CAR encoding mRNA into human T cells, we evaluated for CAR persistence, markers of T cell exhaustion, and cellular cytotoxicity against four primary and two isogenic neuroblastoma cell lines and three primary HGG cell lines. All four constructs showed >80% CAR expression and GPC2-specific binding by flow cytometry. CAR molecules in the light-to-heavy (VL-VH) configuration showed persistence on the surface over seven days and increased cytotoxicity compared to heavy-to-light (VH-VL) configuration. VH-VL configuration with a long linker provided the weakest cytotoxic effect, and evaluation of negative checkpoint regulators revealed the highest expression of PD1 and Lag3 (62% vs. 17–40% in other constructs, p<0.0001). Based on the in vitro data, the two VL-VH CAR constructs were chosen for testing in murine flank models of neuroblastoma treated with IV GPC2 CAR T cells once weekly for three doses. At day 14, animals treated with both VL-VH CAR constructs had reduced tumor burden compared to CD19 CAR controls (p<0.01), with several animals showing complete response. Studies are currently underway evaluating efficacy in orthotopic models of pediatric HGG using local delivery. These data highlight the utility of using mRNA to efficiently design and test novel CAR T cells, providing a platform for clinical testing for proof of efficacy and screening for toxicity.
Delivering high value therapies in COPD: the secret is in the marketing
Authors: Helen Ashdown, Michael Steiner
Journal: European Respiratory Journal (2019)

There are a wide range of therapies now available for people suffering with chronic obstructive pulmonary disease (COPD), both pharmacological and non-pharmacological [1]. However, there has been recent recognition that non-pharmacological approaches (for example smoking cessation and pulmonary rehabilitation) deliver the highest value in terms of patient benefit in relation to cost [2]. It is also evident that the provision of high value therapies in clinical practice is frequently sub-optimal, as illustrated in figure 1 summarising data from a recent, comprehensive primary care audit of COPD care in Wales [3]. The importance of prioritising uptake of high value, non-pharmacological therapies in the management of COPD <http://ow.ly/AA2u30ol4t5>
Progress in the Diagnosis and Treatment of Thoracic Malignancies Continues Unabated
Authors: Alex A. Adjei
Journal: Journal of Thoracic Oncology (2019)

When I was a medical oncology fellow in the 1990s, our approach to treatment of metastatic lung cancer was observation, with the institution of systemic chemotherapy only when patients became symptomatic. This was because the systemic chemotherapy agents available at that time were toxic and only minimally effective. Thus, there was a consensus that the therapy was at best, effective only for symptom palliation, with minimal effects on prolongation of survival. It is fair to say that although there was therapeutic nihilism, it was supported by the data available about the outcome of our patients with metastatic lung cancer. Now, fast-forward to 2019. Thoracic malignancies arguably represent the most exciting group of diseases in oncology in terms of therapeutic advances. The genomic revolution has led to the development of effective, minimally toxic agents for the therapy of a number of molecular aberrations in lung cancer, including ALK receptor tyrosine kinase (ALK), ROS1, RET, and neurotropic tropomyosin receptor kinase gene (NTRK) rearrangements, as well as EGFR, BRAF, and MNNG HOS Transforming gene (c-MET) mutations. There are exciting new agents targeting putative drivers of the malignant phenotype in mesothelioma, such as mesothelin, arginine deprivation therapy, and oncolytic viruses.1Mutti L. Peikert T. Robinson B.W.S. et al.Scientific advances and new frontiers in mesothelioma therapeutics.J Thorac Oncol. 2018; 13: 1269-1283Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar In addition, in the last few years, immunotherapy has revolutionized the care of patients with thoracic malignancies. In NSCLC, immune checkpoint inhibitors are approved by regulatory agencies in the first- and second-line metastatic settings, as well as for locally advanced disease after chemoradiation. There are ongoing clinical trials in the adjuvant and neoadjuvant settings as well. In SCLC, the checkpoint inhibitors are approved in the third-line setting and in the frontline setting in combination with chemotherapy. Promising activity of the checkpoint inhibitors has been observed in mesothelioma and thymoma. It is important for health care professionals to keep up with all these exciting advances. To assist our readers, the International Association for the Study of Lung Cancer has assembled a number of expert physicians and scientists to review the major advances in a number of areas in thoracic malignancies in 2018. These review articles will cover SCLC, mesothelioma, and early-stage and advanced-stage NSCLC, as well as prevention and early detection of lung cancer. The present volume includes an outstanding review on the advances in SCLC. This is the first article in the series. The others will be published over the next several months. We hope that our readers will find the articles in this series an educational resource on the current state of the science and therapeutic options for thoracic malignancies.
INDIVIDUALS' PREFERENCES FOR ESOPHAGEAL CANCER SCREENING STRATEGIES: A DISCRETE CHOICE EXPERIMENT
Authors: Y Peters, E van Grinsven, M van de Haterd, D van Lankveld, J Verbakel, PD Siersema
Journal: Endoscopy (2019)

Screening for esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus could possibly reverse the increasing incidence of EAC. Our objective was to determine individuals' preferences for EAC screening and to assess to what extent procedural characteristics of screening tests predict willingness for screening participation.
Abstract 17107: Virtual Crossmatch May Render Desensitization Therapy Obsolete in Status 1 Patients Awaiting Heart Transplant
Authors: Christopher T Vanichsam, Nancy Reinsmoen, Frank Liou, Zhe Yu, Jamie Yabuno, Jignesh Patel, Michelle Kittleson, Michele Hamilton, David Chang, Lawrence Czer, Jon Kobashigawa
Journal: Circulation (2014)

Purpose: Sensitized patients (pts) awaiting heart transplant (HTx) are purported to have a longer waiting time because of a shrinking donor pool due to unacceptable antigens. The virtual crossmatch...
LGG-13. PAPILLARY GLIONEURONAL TUMOR (PGNT) EXHIBITS A CHARACTERISTIC METHYLATION PROFILE AND MANDATORY FUSIONS INVOLVING PRKCA
Authors: Yanghao Hou, Jorge Pinheiro, Felix Sahm, Stefan M Pfister, David T W Jones, Luca Bertero, Andreas von Deimling
Journal: Neuro-Oncology (2019)

Papillary glioneuronal tumor (PGNT) predominantly arises in children, adolescents and young adults. Its diagnosis poses a major diagnostic challenge. Recently, SLC44A1-PRKCA fusions have been described in PGNT. We subjected 28 brain tumors from different institutions histologically diagnosed as PGNT to molecular analysis and morphological analysis. Array-based methylation analysis revealed that 17/28 tumors exhibited methylation profiles typical for other tumor entities, mostly dysembryoplastic neuroepithelial tumor and hemispheric pilocytic astrocytoma. Conversely, 11/28 tumors exhibited a unique profile thus constituting a distinct methylation class PGNT. By screening the extended Heidelberg cohort containing over 25000 CNS tumors, we identified three additional tumors belonging to this methylation cluster, but originally histologically diagnosed otherwise. RNA sequencing for the detection of SLC44A1-PRKCA fusions could be performed on 19 of the tumors, 10 of them belonging to the methylation class PGNT. In two additional cases, SLC44A1-PRKCA fusions were confirmed by FISH. We detected fusions involving PRKCA in all of the cases of this methylation class with material available for analyses: the canonical SLC44A1-PRKCA fusion was observed in 11/12 tumors, while the remaining case exhibited a NOTCH1-PRKCA fusion. Neither of the fusions was found in the tumors belonging to other methylation classes. Our results point towards a high misclassification rate of the morphological diagnosis PGNT and clearly demonstrate the necessity of molecular analyses. PRKCA fusions are highly diagnostic for PGNT and detection by RNA sequencing allows identification of rare fusion partners. Methylation analysis recognizes a unique methylation class PGNT irrespective of the nature of the PRKCA Fusion.
Morbidity and mortality of candidaemia in Europe: an epidemiologic meta-analysis
Authors: P. Koehler, M. Stecher, O.A. Cornely, D. Koehler, M.J.G.T. Vehreschild, J. Bohlius, H. Wisplinghoff, J.J. Vehreschild
Journal: Clinical Microbiology and Infection (2019)
Rapid Blood Pressure Reduction Safe for Ischemic Stroke
Authors: Anita Slomski
Journal: JAMA (2019)

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EPEN-11. PROTEASOME AND HDAC INHIBITORS ARE CYTOTOXIC AGAINST RELA-FUSION PEDIATRIC EPENDYMOMA CELLS
Authors: Marissa Campagna, Xiangjuan Ma, Lauren McCarl, Rajeev Kumar, Alberto Broniscer, Sameer Agnihotri, James Felker, Ian Pollack, Gary Kohanbash
Journal: Neuro-Oncology (2019)

Ependymomas are the third most common pediatric brain tumor. Nine ependymoma subgroups have been described based on tumor location and genetics. Of supratentorial ependymomas, the C11orf95-RELA fusion (ST-EPN-RELA) subgroup is the most aggressive. The RELA encoded protein is an NF-κB transcription factor family member and activates NF-κB signaling. It has been reported that NF-κB and other pathways are important for ST-EPN-RELA tumors. We therefore hypothesized that ST-EPN-RELA cells may be sensitive to NF-κB signaling cascade inhibitors. To test our hypothesis we evaluated the cytotoxicity of multiple NF-kB signaling inhibitors on DKFZ-EP1NS RELA-fusion positive ependymoma cells and on our established patient-derived ST-EPN-RELA line (CPITT-1). Cells were treated with a single drug or combinations of drugs at concentrations ranging from 10 µM- 0.01 nM for 3–4 days and a WST-1 assay was used to assess viability. Of multiple inhibitors initially tested, Trichostatin A, a histone deacetylase (HDAC) inhibitor, in combination with MG-132, a proteasome inhibitor, displayed the highest level of cytotocity against both RELA-fusion lines. These findings led us to test clinically applicable drugs, including Marizomib, a brain penetrant proteasome inhibitor, and HDAC inhibitors, Panobinostat and Valproic acid. For DKFZ-EP1NS cells, the IC50 for Marizomib alone was 40.82 nM, Marizomib in combination with Panobinostat had an IC50 of 7.4 nM, and Marizomib in combination with Valproic Acid had an IC50 of 44.19. For CPITT-1 cells, the IC50 for Marizomib alone was 25.8nM, Marizomib in combination with Panobinostat had and IC50 of 3.07 nM, and Marizomib in combination with Valproic Acid had an IC50 of 27.04 nM. Overall, we observed that combination of proteasome and HDAC inhibitors are highly toxic to the RELA-fusion ependymoma cells tested. Further studies are warranted to evaluate the use these inhibitors for treating ST-EPN-RELA tumors.
THER-31. TARGETING THE HISTONE DEMETHYLASE LSD1 FOR SELECTIVE APOPTOSIS AND IMMUNE-SENSITIZATION IN PEDIATRIC DIPG
Authors: Cavan Bailey, Bridget Kennis, Megan Romero, Ruolan Han, Jeffrey Larson, Oren Becher, Michelle Monje, Vidya Gopalakrishnan, Wafik Zaky, Dean Lee, Joya Chandra
Journal: Neuro-Oncology (2019)

Pediatric midline gliomas, mainly DIPGs, are a rare and deadly cancer of early childhood, with a 9-month median survival post-diagnosis and a 2-year survival rate of <10%. Their growth on the brainstem makes surgical resection nearly impossible and radiation is primarily palliative. Epigenetic therapies have shown pre-clinical promise in patient-derived DIPG models, however the H3K4 demethylase LSD1 remains an unexplored target in this disease. Clinical trials of LSD1 inhibitors (LSD1i) are currently underway in AML, Ewing’s sarcoma, lung, and prostate cancers. In our studies, treatment with LSD1 inhibitors tranylcypromine (TCP) (IC50: ~1.5mM), GSK LSD1 (IC50: ~400uM), RN-1 (IC50: ~60uM), and SP-2509 or its clinical successor Seclidemstat (SP-2577) (IC50: ~13uM) is selectively cytotoxic to DIPG cells over normal human astrocytes (NHA). Cellular thermal shift assay (CETSA) confirms target engagement of TCP-derived LSD1 inhibitors in DIPG cells at therapeutically relevant doses. Epigenetic therapies can also change the transcriptome of cells, so we mined our previously published RNA-Seq data for potential combination therapy approaches with LSD1 inhibitors. Pathway analysis revealed immune response genes to be significantly changed by LSD1 knockdown. Sub-cytotoxic LSD1i treatment can replicate these changes in DIPG cells but not normal human astrocytes. Pre-treatment of DIPG enhances lysis by NK cells but not T-cells, and the novel genes LCP1/IL18/LAT2 are highly correlated with increasing NK lysis. Using a clustering algorithm in a dataset of 247 pediatric high-grade gliomas, a 13-gene upregulation signature correlates with increased survival and inversely correlates with LSD1 expression (p = 0.0087, unpaired T-test). Immunocompetent murine models of DIPG that possess the H3-K27M mutation and display highly similar LSD1i sensitivity to human DIPG in vitroare currently being dosed in vivo. Our findings support that LSD1 can be targeted in DIPG for both direct cytotoxicity and as a transcriptional modifier in combination with immunotherapy regimens.
IMMU-16. GUADECITABINE (SGI-110) IMMUNOSENSITIZES MURINE C57BL/6-SYNGENEIC GLIOMA AND DIPG MODELS
Authors: Lauren McCarl, Rajeev Kumar, Shubhanchi Nigam, Alberto Broniscer, Sameer Agnihotri, Barry Edwards, Katherine Warren, Ian Pollack, Gary Kohanbash
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) is one of the most lethal pediatric brain tumors. DIPG is insensitive to chemotherapy and surgically inaccessible, creating an urgent need for novel therapeutic approaches. We have been evaluating peptide vaccine immunotherapies that target glioma-associated antigens (GAAs). Enhancing the expression of these immunogenic GAAs and MHC I on tumor cells may promote immune-mediated tumor recognition and killing following peptide vaccine immunotherapy. DNA methyltransferase (DNMT) inhibitors have been shown to augment the expression of MHC, tumor antigens, and other immunosensitizing molecules. Guadecitabine (SGI-110), a next-generation DNMT inhibitor, has been developed to prolong tumor cell exposure to its active metabolite, decitabine. In this study, we investigated whether SGI-110 can immunosensitize glioma cells to peptide vaccine immunotherapy by enhancing their surface expression of MHC I and a GAA, EphA2. We developed a novel C57BL/6-syngeneic DIPG model by culturing cells from a Sleeping Beauty de novo DIPG induced in a neonatal mouse using a K27M-mutated histone 3.3 plasmid and other oncogenic plasmids (SB-DIPG-11). Flow cytometry analysis showed that SB-DIPG-11 cells express both MHC I (H-2Kb/H-2Db) and EphA2 on their surface. In vitro, treatment of SB-DIPG-11 or C57BL/6-syngeneic GL261 cells with SGI-110 resulted in a dose-dependent increase of MHC I and EphA2 surface expression. In vivo, subcutaneous administration of SGI-110 in combination with an EphA2-targeted peptide vaccine significantly prolonged the survival of mice bearing orthotopic DIPG-like tumors compared with the control treatment. Analysis of dissociated tumor tissue by flow cytometry showed elevated levels of MHC I and EphA2 in mice receiving SGI-110 or SGI-110 and peptide vaccine. Based on these data, we have begun evaluating SGI-110 with peptide vaccine in a distinct highly immunogenic syngeneic glioma model and whether subcutaneous or intracerebroventricular administration of the drug is more effective. Overall, SGI-110 may sensitize children with DIPG to peptide vaccine immunotherapy.
Role of Serial 68Ga DOTANOC PET-CT Scans in Follow-up of Metastatic Bronchial Carcinoid
Authors: Sarthak Tripathy, Rakesh Kumar
Journal: Clinical Nuclear Medicine (2019)

Neuroendocrine tumors are slow-growing indolent tumors and often present with metastatic disease at the outset. We hereby discuss the Ga DOTANOC PET-CT findings of a 48-year-old man who has underwent lobectomy for bronchial carcinoid and developed multiple metastatic disease thereafter with event-free survival for the last 12 years.
Congo’s fight against Ebola stalls after epidemiologist is shot dead
Authors: Joanne Silberner
Journal: BMJ (2019)

The World Health Organization has halted some of its activities in areas of the Democratic Republic of the Congo (DRC) affected by the Ebola virus until it can ensure the safety of medical staff and others responding to the outbreak.

It said that it was working with the DRC government to review and strengthen security measures, including establishing security perimeters around staff residences and ensuring that staff comply with curfews.

The moves follow the killing on 19 April of Richard Valery Mouzoko Kiboung, …