tbuckley/cabot-search huggingface dataset:
MODL-09. FEASIBILITY OF ACUTE SLICE CULTURE-SINGLE CELL SEQUENCING DRUG SCREENING AS A TOOL TO SELECT THERAPY FOR CHILDREN WITH RELAPSED BRAIN TUMORS
Authors: Bradley Gampel, Luca Szalontay, Wenting Zhao, James Garvin, Chankrit Sethi, Eileen Stark, Peter Sims, Peter Canoll, Stergios Zacharoulis
Journal: Neuro-Oncology (2020)

Abstract Children with relapsed brain tumors are less responsive to treatment. These children often receive therapies without having any robust predictive method of potential benefit. Acute slice culturing(ASC) is a methodology permitting freshly operated tumor to undergo a culturing process preserving the tumor’s micro-environment. With the current study, we investigated the feasibility of obtaining therapeutically meaningful data in a timely manner (3–5 days), performing direct drug testing and single cell sequencing using ASC. Previously, we have combined ex vivo slices of intact, patient-derived Glioblastoma tissue with single-cell RNA-seq for small-scale drug screening and assessment of patient and cell type-specific drug responses. We generated slices from preclinical mouse glioma models and surgical specimens from adult Glioblastoma patients, as well as from children with relapsed Ependymomas, Medulloblastomas, and Gliomas. We demonstrated that these acute slices preserved both the tumor heterogeneity and tumor microenvironment observed in single-cell RNA-seq of cells directly isolated from tumor tissue. Testing drug responses, we then treated tissue slices from the Glioblastoma mouse models and different patients with multiple drugs and combinations. This technique allowed us to identify drug-induced transcriptional responses in specific subpopulations of tumor cells, patient-specific drug sensitivities, and drug effects conserved in both mouse and human tumors. Preliminary data suggests that we can apply this procedure within 5–7 days and provide real-time drug screening/single cell sequencing ASC results to Recurrent/ Progressive pediatric Low-Grade Gliomas, High Grade Gliomas, Ependymomas and Medulloblastomas.
Abstract 14562: Myofibroblast-Derived Exosomes Induce Endothelial Dysfunction
Authors: Prabhat Ranjan, Rajesh Kumari, Jing Li, Raj Kishore, Suresh K Verma
Journal: Circulation (2019)

Introduction: Endothelial cells (ECs) play critical role to maintain the normal heart function. We have previously shown that stress-induced chronic inflammation mediates endothelial cells dysfunct...
Probiotics-derived metabolite ameliorates skin allergy by promoting differentiation of FOXP3+ regulatory T cells
Authors: Hye-Ji Kang, Gi-Cheon Kim, Choong-Gu Lee, Sunhee Park, Garima Sharma, Ravi Verma, Sin-Hyeog Im, Ho-Keun Kwon
Journal: Journal of Allergy and Clinical Immunology (2020)
Outcomes with different administration schedules of bortezomib in bortezomib, lenalidomide and dexamethasone (<scp>VRd</scp>) as first‐line therapy in multiple myeloma
Authors: Joselle Cook, Isla Johnson, Alexandra Higgins, Surbhi Sidana, Rahma Warsame, Wilson Gonsalves, Morie A. Gertz, Francis Buadi, Martha Lacy, Prashant Kapoor, Angela Dispenzieri, Taxiarchis Kourelis, David Dingli, Amie Fonder, Suzanne Hayman, Miriam Hobbs, Yi Lisa Hwa, Robert Kyle, Nelson Leung, Ronald Go, Vincent S. Rajkumar, Shaji Kumar
Journal: American Journal of Hematology (2020)

Induction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment-emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first-line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty-five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21-day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22-56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.
TMOD-18. TARGETING THE PI3K/AKT PATHWAY IN MYCN AMPLIFIED HIGH GRADE GLIOMAS
Authors: Katharine Halligan, Ann-Catherine Stanton, Matthew Halbert, Brian Golbourn, Stephen Mack, Ian Pollack, Sameer Agnihotri
Journal: Neuro-Oncology (2020)

Abstract Pediatric glioblastoma (pGBM) are incurable brain tumors with overall poor prognosis and response to treatments due to molecular and epigenetic heterogeneity. In particular, the MYCN subtype of pGBM are a highly aggressive form of GBM with a dismal median survival of only 14 months. Furthermore, this subtype is enriched with loss of the tumor suppressor genes TP53 and PTEN, leading to aberrantly active PI3K-AKT signaling pathway and DNA-checkpoint abnormalities. Here, we report the generation of a novel syngeneic mouse model that recapitulates the features of the MYCN subtype of pGBM. We isolated Sox2-Cre neural stem cells from C57BL/6 mice and transduced inverted retroviral-cassettes of the murine Mycn oncogene simultaneously with shRNA targeting tumor suppressor genes p53 and Pten. Retroviral-cassettes are flanked by tandem LoxP sites arranged so that Cre recombinase expression inverts the cassettes in frame allowing for MYCN protein expression and loss of the P53/PTEN proteins. Transgene activation is accompanied with selectable cell surface markers and fluorescent tags enabling for fluorescent activated cell sorting (FACS) of the desired cell populations. Neural stem cells with MYCN protein expression and concurrent silencing of P53 and PTEN protein (NPP cells) result in significantly increased proliferation and activation of PI3K-AKT pathway as compared to control neural stem cells and have. Injection of NPP cells into the forebrain of immune competent C57BL/6 mice result in the formation of invasive high-grade gliomas with a lethal phenotype at ~50 days post injection. Using several next generation brain penetrant small molecule inhibitors of the PI3K-AKT pathway, we show inhibition of tumorigenesis in vitro. Moreover, we have identified several novel mechanisms of PI3KAKT treatment resistance and are currently identifying therapies that may overcome this resistance through RNA seq analysis. In summary, well defined genetic drivers of GBM can lead to informed mouse model generation to test promising therapies.
EXTH-56. DISRUPTION OF FUNCTIONAL NETWORKS IN GLIOBLASTOMA TO OVERCOME THERAPY RESISTANCE
Authors: Kevin Joseph, Lea Vollmer, Matthias Schneider, Juergen Beck, Ulrich Hofmann, Oliver Schnell, Dieter Heiland
Journal: Neuro-Oncology (2020)

Abstract Neurobeachin plays a crucial role when it comes to the formation, maturation, and differentiation of functional synapses, within the central nervous system (CNS). Glioblastoma has cellular compartments that have been shown to form functional synapses, integrating themselves to existing neuronal networks. We present evidence that GBM cells form electrophysiologically active networks, mediated by both electrical and chemical synapses during their growth. These networks carry information about changes in the tumor microenvironment, similar to those observed in neuronal networks. We present data about signature signaling patterns, dependent on stimuli, leading to transcriptional changes. These patterns are conducted through the network by means of electrical/chemical synapses, mediated by Neurobeachin. When the tumor network was acutely treated with a signaling inhibitor, Meclofenamate, functional synapses were altered, leading to an abolishment of electrical signaling, resulting in loss of biological organization. These results were validated in both extracellular electrophysiological recordings and Ca2+ imaging experiments. The formation of these functional networks plays a vital role in the resistance to alkylating agents or harsh metabolic imbalances, which was completely lost when the network was disrupted. Acute downregulation of Neurobeachin expression causes electrophysiological disruption of the GBM network, leading to loss of connectivity, terminally resulting in cell apoptosis/necrosis, transcriptionally validated by means of RNA-seq. This combined therapeutic approach could lead to potential alternative therapy, where the basic biological functionality of the GBM is targeted.
NIMG-09. PREDICTING OVERALL SURVIVAL OF GLIOBLASTOMA PATIENTS ON MULTI-INSTITUTIONAL HISTOPATHOLOGY STAINED SLIDES USING DEEP LEARNING AND POPULATION-BASED NORMALIZATION
Authors: Jie Hao, Jose Agraz, Caleb Grenko, Ji Won Park, Angela Viaene, Maclean Nasrallah, Dokyoon Kim, Spyridon Bakas
Journal: Neuro-Oncology (2020)

Abstract MOTIVATION Glioblastoma is the most common and aggressive adult brain tumor. Clinical histopathologic evaluation is essential for tumor classification, which according to the World Health Organization is associated with prognostic information. Accurate prediction of patient overall survival (OS) from clinical routine baseline histopathology whole slide images (WSI) using advanced computational methods, while considering variations in the staining process, could contribute to clinical decision-making and patient management optimization. METHODS We utilize The Cancer Genome Atlas glioblastoma (TCGA-GBM) collection, comprising multi-institutional hematoxylin and eosin (H&amp;E) stained frozen top-section WSI, genomic, and clinical data from 121 subjects. Data are randomly split into training (80%), validation (10%), and testing (10%) sets, while proportionally keeping the ratio of censored patients. We propose a novel deep learning algorithm to identify survival-discriminative histopathological patterns in a WSI, through feature maps, and quantitatively integrate them with gene expression and clinical data to predict patient OS. The concordance index (C-index) is used to quantify the predictive OS performance. Variations in slide staining are assessed through a novel population-based stain normalization approach, informed of glioblastoma distinct histologic sub-regions and their appearance from 509 H&amp;E stained slides with corresponding anatomical annotations from the Ivy Glioblastoma Atlas Project (IvyGAP). RESULTS C-index was equal to 0.797, 0.713, and 0.703 for the training, validation, and testing data, respectively, prior to stain normalization. Following normalization, staining variations in H&amp;E and ‘E’ gained significant improvements in IvyGAP (pWilcoxon&amp;lt; 0.01) and TCGA-GBM (pWilcoxon&amp;lt; 0.0001) data, respectively. These improvements contributed to further optimizing the C-index to 0.871, 0.777, and 0.780 for the training, validation, and testing data, respectively. CONCLUSIONS Appropriate normalization and integrative deep learning yield accurate OS prediction of glioblastoma patients through H&amp;E slides, generalizable in multi-institutional data, potentially contributing to patient stratification in clinical trials. Our computationally-identified survival-discriminative histopathological patterns can contribute in further understanding glioblastoma.
COVID-19 Myocardial Pathology Evaluation in Athletes With Cardiac Magnetic Resonance (COMPETE CMR)
Authors: Daniel E. Clark, Amar Parikh, Jeffrey M. Dendy, Alex B. Diamond, Kristen George-Durrett, Frank A. Fish, James C. Slaughter, Warne Fitch, Sean G. Hughes, Jonathan H. Soslow
Journal: Circulation (2020)

remains imperative when contextualizing abnormal CMR findings in the adjudication of a safe return to athletic competition.Ongoing investigations of the short-and long-term cardiovascular manifestations of COVID-19 are necessary to inform the optimal care of athletes recovering from infection.
RARE-22. GERMLINE PATHOGENIC VARIANT c.1552G&amp;gt;A;p.E518K IN DGCR8 CONFERS SUSCEPTIBILITY FOR SCHWANNOMATOSIS AND THYROID TUMORS
Authors: Anne-Sophie Chong, Javad Nadaf, Elia Grau, Maria Apellaniz-Ruiz, Somayyeh Fahiminiya, Avi Saskin, HyeRim Han, Robert Turcotte, Karl Muchantef, Christian Thomas, Rabea Wagener, Angelia Bassenden, Ozgur Mete, Marc Pusztaszeri, Werner Paulus, Albert Berghuis, Reiner Siebert, Steffen Albrecht, Martin Hasselblatt, Conxi Lazaro, Alexander Teule, Marc Fabian, Joan Brunet, William Foulkes, Barbara Rivera
Journal: Neuro-Oncology (2020)

Abstract Germline mutations in DICER1 cause a pleiotropic susceptibility syndrome characterized by the development of pediatric or early-onset tumors including pleuropulmonary blastoma, Wilms tumors, pineoblastomas, multinodular goiter (MNG) and thyroid cancers. Somatic mutations in the other two microprocessors DROSHA and DGCR8 have been found in Wilms Tumors and pineoblastomas. We present here two families with peripheral schwannomatosis and thyroid tumors carrying a germline variant c.1552G&amp;gt;A;p.E518K in DGCR8. Family one had six affected members with early-onset MNG and five of them developed schwannomatosis. All five members were heterozygous for the variant. One of the carriers had also been diagnosed with a choroid plexus papilloma at 7 years old. The common second event in all tumors tested was the loss of chromosome 22 at the somatic level. In family two, a 35-year-old male was diagnosed with a peripheral schwannoma at the age of 12. Since then, he has developed seven extra peripheral schwannomas (one of which was an ancient schwannoma) and papillary thyroid cancer. DGCR8 lies on chromosome 22q, adjacent to the three schwannoma genes: LZTR1, SMARCB1 and NF2. The variant, c.1552G&amp;gt;A;p.E518K localizes to the first RNA-binding domain of DGCR8 and structural modelling predicts that it abolishes proper binding of RNA. It is also a hotspot somatic mutation in Wilms tumors. Using miRNA profiling, we show that this variant disrupts global microRNA production and DGCR8 mutated tumors show a specific miRNA profile different from DGCR8 wild type tumors. These findings reinforce DGCR8 as a novel susceptibility gene for schwannomatosis and thyroid tumors.
H19 Promotes HCC Bone Metastasis Through Reducing Osteoprotegerin Expression in a Protein Phosphatase 1 Catalytic Subunit Alpha/p38 Mitogen‐Activated Protein Kinase–Dependent Manner and Sponging microRNA 200b‐3p
Authors: Zhao Huang, Liang Chu, Junnan Liang, Xiaolong Tan, Yu Wang, Jingyuan Wen, Jin Chen, Yu Wu, Sha Liu, Jingyu Liao, Rui Hou, Zeyang Ding, Zhanguo Zhang, Huifang Liang, Shasha Song, Caihong Yang, Jinming Zhang, Tao Guo, Xiaoping Chen, Bixiang Zhang
Journal: Hepatology (2020)

Bone is the second most frequent site of metastasis for HCC, which leads to an extremely poor prognosis. HCC bone metastasis is typically osteolytic, involving the activation of osteoclasts. Long noncoding RNA H19 plays an important role in the pathogenesis of human cancers. Nonetheless, the mechanism underlying the participation of H19 in HCC bone metastasis remains unclear.The current study established a mouse HCC bone metastasis model by using serial intracardiac injection and cell isolation to obtain cells with distinct bone metastasis ability. H19 was highly expressed in these cells and in clinical HCC bone metastasis specimens. Both osteoclastogenesis in vitro and HCC bone metastasis in vivo were promoted by H19 overexpression, whereas these processes were suppressed by H19 knockdown. H19 overexpression attenuated p38 phosphorylation and further down-regulated the expression of osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor. However, up-regulated OPG expression as well as suppressed osteoclastogenesis caused by H19 knockdown were recovered by p38 interference, indicating that p38 mitogen-activated protein kinase (MAPK)-OPG contributed to H19-promoted HCC bone metastasis. Furthermore, we demonstrated that H19 inhibited the expression of OPG by binding with protein phosphatase 1 catalytic subunit alpha (PPP1CA), which dephosphorylates p38. SB-203580-mediated inactivation of p38MAPK reversed the down-regulation of HCC bone metastasis caused by H19 knockdown in vivo. Additionally, H19 enhanced cell migration and invasion by up-regulating zinc finger E-box binding homeobox 1 through the sequestration of microRNA (miR) 200b-3p.H19 plays a critical role in HCC bone metastasis by reducing OPG expression, which is mediated by the PPP1CA-induced inactivation of the p38MAPK pathway; and H19 also functions as a sponge for miR-200b-3p.
EXTH-49. BXQ-350 TARGETS TO THE LYSOSOME AND KILLS GLIOBLASTOMA (GBM) CELLS VIA ACTIVATION OF APOPTOTIC CASPASES IN VITRO
Authors: Nikhil Wilkins, Timothy Stephens, Laura Felix
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Apoptosis is a programmed cell death mechanism where cells respond to internal or external stimuli by initiating a cascade of events and enzymes leading to cell death. One of the hallmarks of cancer is the ability to resist apoptotic stimuli. Removing resistances to apoptosis can result in the death of these tumor cells. METHOD The GBM cell line Gli36ΔEGFR was used to determine Caspase activity and BXQ-350 cytotoxicity. Cells were treated with 9uM to 30uM BXQ-350 in triplicate and incubated for 24 hours at 37oC. Promega’s Caspase-Glo 9 or Caspase-Glo 3/7 reagent was added to each well of a plate and was incubated at room temperature in the dark for 3 hours then luminescence was read. The parallel cytotoxic assay was run under the same conditions except Roche’s MTT labeling reagent was added to each well after 24 hours and the plate was incubated at 370C for 4 hours. Solubilization solution was added to each well, the plate was incubated overnight then absorbance was read. The GBM cell line U87 MG was used to determine lysosomal targeting by treating with 10uM BXQ-350 and incubated at 37oC overnight. They were stained with anti-SapC (RFP) and anti-LAMP1 (GFP) antibodies and images were taken. RESULT BXQ-350 mediated cell death is correlated with a rise in Caspase 3, Caspase 7 and Caspase 9 activity. The caspase activity levels did not rise until after BXQ-350 passed its IC50 and stayed elevated. Caspases 3/7 levels showed higher activity compared to untreated than Caspase 9. BXQ-350 was seen to colocalize to LAMP1, a lysosomal membrane protein. CONCLUSION BXQ-350 tracks to the lysosomal membrane where it initiates a cascade of enzymes necessary to cause apoptosis. Caspases 3/7 are the effector caspases that complete the apoptotic process removing a major barrier to fight cancer.
Abstract 17016: Cardiovascular Safety Profile of Gonadotropin Releasing Hormone (GnRH) Antagonist Compared to GnRH Agonist Among Patients With Prostate Cancer: A Meta-Analysis
Authors: Courtney Campbell, Daniel Addison, Ragavendra Baliga, Ajay Vallakati
Journal: Circulation (2020)

Introduction: Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer therapy. The degree that ADT contributes to cardiovascular disease remains uncertain with conflicting studies. ADT can be achieved through the use of gonadotrophin releasing (GnRH) hormone agonist or, more recently, GnRH antagonists. The objective of this study was to determine whether cardiovascular events differ after the initiation of GnRH agonist compared with GnRH antagonist in randomized control trials. Methods: From PubMed, Cochrane Central, and Embase we identified all randomized studies comparing GnRH antagonists with GnRH agonists in patients with prostate cancer from 2000-2020. Outcomes studied included major adverse cardiovascular events (MACE), coronary artery disease (CAD), cerebrovascular accidents (CVA), atrial fibrillation (AF), and heart failure (HF). A random effects model using the Mantel-Haenszel method was used to assess outcomes. Results: Overall, we identified 7 studies (n = 3298) which reported outcomes in prostate cancer patients receiving GnRH antagonists (n = 2127) compared with those receiving GnRH agonists (n = 1171). When compared to men receiving GnRH agonists, the incidence of MACE (RR 0.52, 95% CI 0.35-0.76, p&lt;0.001) and CAD (RR 0.46, 95% CI 0.27 - 0.77, p=0.004) was lower in men receiving GnRH antagonists. There was no difference in the rates of CVA (RR 0.93, 95% CI 0.31-2.77, p=0.89), AF (RR 0.49, 95% CI 0.09-2.72, p=0.41), or HF (RR 0.55, 95% CI 0.19-1.59, p=0.52) between the two groups. Conclusion: For men with prostate cancer receiving ADT, GnRH antagonists decreased the incidence of MACE and coronary artery disease by half compared to men treated with GnRH agonists. GnRH antagonists have a more favorable cardiovascular safety profile than GnRH agonists.
Altered Regulation of HIF-1α in Naive- and Drug-Resistant EGFR-Mutant NSCLC: Implications for a Vascular Endothelial Growth Factor-Dependent Phenotype
Authors: Monique B. Nilsson, Jacqulyne Robichaux, Matthew H. Herynk, Tina Cascone, Xiuning Le, Yasir Elamin, Sonia Patel, Fahao Zhang, Li Xu, Limei Hu, Lixia Diao, Li Shen, Junqin He, Xiaoxing Yu, Petros Nikolinakos, Pierre Saintigny, Bingliang Fang, Luc Girard, Jing Wang, John D. Minna, Ignacio I. Wistuba, John V. Heymach
Journal: Journal of Thoracic Oncology (2020)