tbuckley/cabot-search huggingface dataset:
MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
Authors: Melissa Galati, Li Li, Sumedha Sudhaman, Tatiana Lipman, Lucie Stengs, Dana Elshaer, Taylor Bridge, Dar’ya Semenova, Melissa Edwards, Karl Hodel, Victoria J Forster, Nuno M Nunes, Alberto Martin, Eric Bouffet, Zachary Pursell, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2020)

Abstract Replication repair deficiency (RRD) is the leading cause of hypermutant brain tumours in children. RRD is caused by defects in one of four mismatch repair (MMR) genes and mutations in POLE or POLD1. Such tumours are resistant to common therapeutic agents and animal models are needed to study RRD in vivo and test novel therapies like immune checkpoint inhibitors (ICIs). To model RRD brain tumours specifically, we engineered a Pole mutant mouse model harbouring the S459F mutation (PoleS459F). We combined PoleS459F mice with conditional Msh2 knockout (Msh2LoxP) and Nestin-cre mice. All Nestin-cre+Msh2LoxP/LoxPPoleS459F/+ mice rapidly succumbed to posterior fossa brain tumours between 8.6 and 12.4 weeks. Importantly, tumours exhibited hallmark “ultrahypermutation” (~350 mutations/Mb) and the corresponding signatures characteristic of human combined MMR and POLE-proofreading glioblastoma. Interestingly, Nestin-cre+Msh2LoxP/LoxPPoleS459F/S459F mice failed to establish normal cerebella, suggesting such mutational loads may not support normal brain development. Furthermore, OLIG2-cre+Msh2LoxP/LoxPPoleS459F/+ mice failed to develop tumors. Tumors transplanted into syngeneic vs immunocompromised animals egrafted well orthotopically in the mouse hindbrain but significantly less efficiently when engrafted subcutaneously. Furthermore, immunocompromised and subcutaneous tumors revealed striking differences in mutational burden and clonal architecture, suggestive of nonautonomous immunoediting. Finally, anti-PD1 was sufficient to treat subcutaneously engrafted tumors in immunocompetent animals. This first mouse model of immunocompetent, hypermutant brain tumors can be used to uncover unique characteristics of RRD tumour evolution and allow for immune based therapeutic preclinical testing. Experiments to assess combinational ICIs and other therapeutic interventions in orthotopically transplanted tumors will also be presented.
Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma: Is It Time to Consider CAR-T for All?
Authors: Andrew D. Zelenetz
Journal: Journal of the National Comprehensive Cancer Network (2020)

CAR T cells have demonstrated activity in relapsed/refractory non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), indolent non-Hodgkin lymphoma, and mantle cell lymphoma. For patients with chemorefractory disease, CAR T cells can provide a durable complete response in a portion of patients, which represents a major advance in the field. For patients with chemosensitive disease, however, additional data are needed to determine whether CAR T cells are preferable to conventional approaches. Studies in DLBCL have shown that patients experiencing a PET-positive partial response after second-line chemotherapy have long-term outcomes after high-dose therapy and autologous stem cell rescue that are similar to CAR T-cell therapy, with decreased toxicity and cost. Alternative third-line options such as tafasitamab/lenalidomide and bispecific antibodies may also have a role for patients with chemorefractory disease.
EXTH-18. ENGINEERED EXOSOMES AS GENE DELIVERY TOOLS FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Malcolm McDonald, Anwar Hossain, Eric Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Marc Daou, Sricharan Gopakumar, Lynette Phillips, Brittany Parker Kerrigan, Frederick Lang
Journal: Neuro-Oncology (2020)

Abstract Although we previously showed that exosomes are capable of delivering anti-glioma microRNAs (miRs) to brain tumors (Lang et al. 2018), our studies revealed significant opportunity to 1) improve packaging and delivery efficiency of exosomes and 2) expand the repertoire of anti-glioma miRs. We hypothesized that incorporation of viral proteins into exosomes would enhance miR packaging and cell entry. To test this hypothesis, we engineered exosomes that express retroviral Gag and VSVg proteins (eExos). Specifically, HEK293T cells were transfected with Gag, VSVg, and with Cre-recombinase containing plasmid (pCre) to generate eExos-pCre. After 48hrs eExos-pCre were isolated by differential ultracentrifugation. Western analyses verified Gag and VSVg in eExos-pCre, and PCR documented pCre in these exosomes. Next, U87 cells harboring a dsRed-eGFP-loxP reporter-gene were treated with eExos-pCre or control exosomes. Flow cytometry demonstrated that eExos-pCre resulted in 82% conversion of red cells to green, compared with controls (2% conversion), verifying the effectiveness of eExos to deliver plasmids containing anti-glioma agents. To identify effective anti-glioma miRs, we conducted a high-throughput screen of 539 miRs against 7 glioma stem cell lines (GSCs) and identified miR-124-2, miR-135-a-2, and Let7i as the most potent anti-glioma miRs. We then studied the ability of eExos to package and deliver plasmids of these miRs either singly (eExos-miR-124, eExos-miR-135, eExos-miRLet7i) or as a tri-cistronic plasmid (eExos-miR-124-135-Let7i). Although eExos-miR-124, eExos-miR-135, and eExos-miRLet7i significantly decreased in vitro proliferation in all three GSCs (p&amp;lt; 0.01), eExos-miR-124-135-Let7i were most effective (p&amp;lt; 0.001). In in vivo studies, mice harboring GSC231 gliomas were injected with each of the eExos-miRs. Most significant improvement in survival was seen with eExos-miR-124-135-Let7i (median 75 versus 32.5 days for controls, p&amp;lt; 0.001). We conclude that eExos are a novel delivery strategy for human gliomas and that a tri-cistronic plasmid of miR-124-135-Let7i is highly effective against GBM and worthy of clinical translation.
Evaluation of diagnostic criteria for borderline personality disorder
Authors: H G Nurnberg, S W Hurt, A Feldman, R Suh
Journal: American Journal of Psychiatry (1988)

A comparison of 17 narrowly defined borderline patients with 20 nonpatient control subjects indicated that certain individual and combinations of criteria may be more highly correlated with the disorder than others. Requiring any four or certain specific combinations of two or three of the five most discriminating criteria provided the optimal balance of sensitivity, specificity, predictive power, and diagnostic efficiency considerations. Fewer than five DSM-III-R criteria adequately identified the patients.
Imaging atherosclerotic plaques by targeting Galectin-3 and activated macrophages using (<sup>89</sup>Zr)-DFO- Galectin3-F(ab')<sub>2</sub> mAb
Authors: Zohreh Varasteh, Francesco De Rose, Sarajo Mohanta, Yuanfang Li, Xi Zhang, Benedikt Miritsch, Giorgia Scafetta, Changjun Yin, Hendrik B. Sager, Sarah Glasl, Dimitris Gorpas, Andreas J.R. Habenicht, Vasilis Ntziachristos, Wolfgang A. Weber, Armando Bartolazzi, Markus Schwaiger, Calogero D'Alessandria
Journal: Theranostics (2020)

Rationale: The high expression of Galectin-3 (Gal3) in macrophages of atherosclerotic plaques suggests its participation in atherosclerosis pathogenesis, and raises the possibility to use it as a target to image disease severity in vivo. Here, we explored the feasibility of tracking atherosclerosis by targeting Gal3 expression in plaques of apolipoprotein E knockout (ApoE-KO) mice via PET imaging. Methods: Targeting of Gal3 in M0-, M1- and M2 (M2a/M2c)-polarized macrophages was assessed in vitro using a Gal3-F(ab')2 mAb labeled with AlexaFluor®488 and 89Zr- desferrioxamine-thioureyl-phenyl-isothiocyanate (DFO). To visualize plaques in vivo, ApoE-KO mice were injected i.v. with 89Zr-DFO-Gal3-F(ab')2 mAb and imaged via PET/CT 48 h post injection. Whole length aortas harvested from euthanized mice were processed for Sudan-IV staining, autoradiography, and immunostaining for Gal3, CD68 and α-SMA expression. To confirm accumulation of the tracer in plaques, ApoE-KO mice were injected i.v. with Cy5.5-Gal3-F(ab')2 mAb, euthanized 48 h post injection, followed by cryosections of the body and acquisition of fluorescent images. To explore the clinical potential of this imaging modality, immunostaining for Gal3, CD68 and α-SMA expression were carried out in human plaques. Single cell RNA sequencing (scRNA-Seq) analyses were performed to measure LGALS3 (i.e. a synonym for Gal3) gene expression in each macrophage of several subtypes present in murine or human plaques. Results: Preferential binding to M2 macrophages was observed with both AlexaFluor®488-Gal3-F(ab')2 and 89Zr-DFO-Gal3-F(ab')2 mAbs. Focal and specific 89Zr-DFO-Gal3-F(ab')2 mAb uptake was detected in plaques of ApoE-KO mice by PET/CT. Autoradiography and immunohistochemical analyses of aortas confirmed the expression of Gal3 within plaques mainly in macrophages. Moreover, a specific fluorescent signal was visualized within the lesions of vascular structures burdened by plaques in mice. Gal3 expression in human plaques showed similar Gal3 expression patterns when compared to their murine counterparts. Conclusions: Our data reveal that 89Zr-DFO-Gal3-F(ab')2 mAb PET/CT is a potentially novel tool to image atherosclerotic plaques at different stages of development, allowing knowledge-based tailored individual intervention in clinically significant disease.
Abstract 11247: Application of the H2FPEF-score to the Community: The Aric Study
Authors: Senthil Selvaraj, Peder Myhre, Muthiah Vaduganathan, Brian Claggett, Amil M Shah, Scott D Solomon
Journal: Circulation (2019)

Background: The H2FPEF-score has been proposed to estimate the likelihood of HFpEF among patients with unexplained dyspnea, but its prognostic relevance in older community-based persons is not know...
SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies
Authors: Mahesh Saqcena, Luis Javier Leandro-Garcia, Jesper L.V. Maag, Vatche Tchekmedyian, Gnana P. Krishnamoorthy, Prasanna P. Tamarapu, Vera Tiedje, Vincent Reuter, Jeffrey A. Knauf, Elisa de Stanchina, Bin Xu, Xiao-Hui Liao, Samuel Refetoff, Ronald Ghossein, Ping Chi, Alan L. Ho, Richard P. Koche, James A. Fagin
Journal: Cancer Discovery (2020)

Abstract Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse BRAFV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAFV600E-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor–based redifferentiation therapies. Significance: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade. This article is highlighted in the In This Issue feature, p. 995
BIOM-25. IDENTIFYING EXTRACELLULAR VESICLES FROM GLIOBLASTOMA OR NON-NEOPLASTIC CELLS VIA IMAGING FLOW CYTOMETRY
Authors: Luz Milbeth Cumba Garcia, Abudumijiti Aibaidula, Nazanin Yeganeh Kazemi, Miyeon Jung, Fabrice Lucien-Matteoni, Svetomir Markovic, Ian Parney
Journal: Neuro-Oncology (2020)

Abstract Patients with glioblastoma (GBM) have a median survival of 15 months despite aggressive treatment. Immunosuppressive monocytes are heavily infiltrated in these tumors and in patients’ circulation. Treatment-related pseudo-progression confounds outcome assessment by MRI. Thus, there is a need for additional non-invasive methods to assess treatment response. Extracellular vesicles (EVs) contain tumor-specific microRNA (miRNA) cargo that could serve as a liquid biopsy to distinguish true progression from treatment-related pseudo-progression. We had found significant differences in plasma EVs molecular profile (i.e. miRNA signatures) between GBM patients and healthy donors. Our overall hypothesis is that these differences reflect the EVs cell of origin. Our goal in this project was to develop a fluorescent staining paradigm by flow cytometry to distinguish EVs from different cells in vitro and determine differences in EV miRNA expression profile between GBM and monocytic cell-derived EVs. Gleolan (5-ALA) is an FDA-approved orally available agent for fluorescence-guided resection of GBM tumors. It is metabolized to protoporphyrin IX (PpIX) in GBM cells but not in non-neoplastic cells and has been reported to aid in the detection of GBM-derived EVs by flow cytometry. However, distinguishing between GBM-derived EVs and EVs from other cells of origin has not been described. We co-cultured human GBM cells (dBT114 or dBT116) and CD14+ monocytes for 72 hours in the presence or absence of 5-ALA. EVs were isolated by ultracentrifugation and stained for CD11b (myeloid cell marker). ImageStream Imaging Flow Cytometry was performed showing clear differentiation between PpIX+ EVs from GBM cells and CD11b+ EVs from monocytes. Interestingly, a small number of double-positive EVs (presumably representing monocyte-derived EVs that had taken up PpIX after phagocytizing GBM cells) were also present. Taken together, we were able to optimize a technique to distinguish EVs originating from GBM and monocytes for further characterization by short non-coding RNA sequencing.
LGG-05. MOLECULAR GUIDED THERAPY FOR A PEDIATRIC LOW GRADE GLIOMA: A CASE REPORT
Authors: Jayne VonBergen, Beth Armstrong, Morgan Schmitt
Journal: Neuro-Oncology (2020)

Abstract Low grade gliomas are the most common type of central nervous system tumors among children. Despite the fact that they are not typically life threatening, low grade gliomas remain a significant clinical challenge. Case Study: Patient is a 4-year-old male who presented at 20 months of age with several weeks of ataxia, emesis, and head tilt. Imaging revealed a right temporal lobe lesion; he was subsequently taken to surgery, where a gross total resection was achieved. Imaging 9 months post resection revealed recurrent disease within the right temporal region with leptomeningeal involvement. Four months later imaging revealed progression of multifocal disease and new growth within the sella. At this time the patient started standard treatment, Carboplatin and Vincristine, per CCG 9952A. Persistent slow progression was observed despite receiving standard therapy. The patient developed a grade 3 reaction to carboplatin, worsening with each subsequent dose. At this time, he was referred to our Precision Genomics Neuro Oncology program for tumor molecular characterization. Somatic tumor testing revealed an ETV6-NTRK3 fusion, at which time standard treatment was stopped, and patient began targeted therapy, Larotrectinib. Imaging was preformed 2 months post start of targeted therapy and revealed interval decrease in size of previously enhancing nodular lesions; findings consistent with treatment response. Disease burden continues to decrease with therapy. This case illustrates a clear benefit of using molecular guided therapy in low grade gliomas.
NCOG-53. PREDICTORS OF ENDOCRINE OUTCOME AFTER ENDOSCOPIC TRANSSPHENOIDAL SURGERY FOR NON-FUNCTIONING PITUITARY ADENOMAS
Authors: Jenie Hwang, Diane Yum, Michael Chicoine, Ralph Dacey, Joshua Osbun, Keith Rich, Gregory Zipfel, Cristine Klatt-Cromwell, Jonathan Mcjunkin, Patrik Pipkorn, John Schneider, Julie Silverstein, Albert Kim
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Although endoscopic transsphenoidal surgery (ETSS) is an established treatment for patients with nonfunctioning pituitary adenomas (NFPAs), data are limited regarding the rates and predictors of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS. OBJECTIVE To analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS Among a cohort of 601 consecutive patients who underwent ETSS for NFPA between 2010 and 2018 at Washington University in Saint Louis, recovery or development of new hypopituitarism was retrospectively analyzed in 209 patients. RESULTS Preoperative endocrine deficits were observed in 59.8% of patients (125/209), and the deficit rates were 76.8% for male gonadal axis (86/112), 42.5% for thyroid axis, 25.8% for growth hormone axis, and 15.8% for cortisol axis. Recovery of preoperative pituitary deficit was noted in all four axes, with highest recovery in the cortisol axis with a 1-year cumulative recovery rate of 44.3%. New-onset postoperative hypopituitarism occurred most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Multivariate analyses revealed axis-specific predictors of postoperative recovery and de novo deficiency. Older age was a negative predictor for recovery of both male hypogonadism (P= 0.04) and adrenal insufficiency (P=0.046), and a larger tumor volume was a negative predictor for recovery of hypothyroidism (P=0.043). Although higher body mass index was generally associated with any new postoperative pituitary deficit (P=0.03), most predictors of new onset deficits also differed by hormone axis. CONCLUSIONS Dynamic changes in pituitary hormonal levels were observed in a significant fraction of patients following ETSS in NFPA patients. The specific hormonal axis dictated postoperative endocrine vulnerability, recovery, and predictors of recovery or loss of endocrine function.
Directly Compressed Tablets: A Novel Drug‐Containing Reservoir Combined with Hydrogel‐Forming Microneedle Arrays for Transdermal Drug Delivery
Authors: Emma McAlister, Bridie Dutton, Lalitkumar K. Vora, Li Zhao, Anastasia Ripolin, Dk Siti Zawanah Binti Pg Hj Zahari, Helen L. Quinn, Ismaiel A. Tekko, Aaron J. Courtenay, Stephen A. Kelly, Aoife M. Rodgers, Lilach Steiner, Galit Levin, Etgar Levy‐Nissenbaum, Nava Shterman, Helen O. McCarthy, Ryan F. Donnelly
Journal: Advanced Healthcare Materials (2020)

Abstract Microneedle (MN) patches consist of a hydrogel‐forming MN array and a drug‐containing reservoir. Drug‐containing reservoirs documented in the literature include polymeric films and lyophilized wafers. While effective, both reservoir formulations are aqueous based, and so degradation can occur during formulation and drying for drugs inherently unstable in aqueous media. The preparation and characterization of novel, nonaqueous‐based, directly compressed tablets (DCTs) for use in combination with hydrogel‐forming MN arrays are described for the first time. In this work, a range of drug molecules are investigated. Precipitation of amoxicillin (AMX) and primaquine (PQ) in conventional hydrogel‐forming MN arrays leads to use of poly(vinyl alcohol)‐based MN arrays. Following in vitro permeation studies, in vivo pharmacokinetic studies are conducted in rats with MN patches containing AMX, levodopa/carbidopa (LD/CD), and levofloxacin (LVX). Therapeutically relevant concentrations of AMX (≥2 µg mL −1 ), LD (≥0.5 µg mL −1 ), and LVX (≥0.2 µg mL −1 ) are successfully achieved at 1, 2, and 1 h, respectively. Thus, the use of DCTs offers promise to expand the range of drug molecules that can be delivered transdermally using MN patches.
NURS-02. CLINICAL MANAGEMENT OF PATIENTS RECEIVING CAR T CELL THERAPY FOR CNS TUMORS
Authors: Susan Holtzclaw, Corrine Hoeppner
Journal: Neuro-Oncology (2020)

Abstract Chimeric antigen receptor (CAR) T cells are an innovative new therapy with proven efficacy in some pediatric cancers such as leukemia and lymphoma, but much less experience in solid tumors, especially tumors of the central nervous system (CNS). Seattle Children’s has three open Phase 1 CAR T cell studies (BrainChild-01, -02, and -03 targeting HER2, EGFR, and B7-H3, respectively) for recurrent/refractory CNS tumors and DIPG (BrainChild-03 only). As of December 2019, four patients have been treated at Seattle Children’s Hospital with CAR T cells infused on a weekly schedule through indwelling catheters into the tumor resection cavity or ventricular system. Given the scrutiny of clinical care needed for Phase 1 studies, we are now able to report detailed clinical information that we have learned during the treatment of these patients. Clinical care includes the judicious use of steroids, the clinical support of patient’s symptoms pre- and post-infusion, and the management of peritumoral edema. We will also discuss the psychosocial support needed for families who travel long distances to receive this therapy compounded by the many emotional components of being enrolled on any Phase 1 trial. Case studies and experience from a Nurse Practitioner role will be provided and discussed.
AB0020 Comparison of synovial mmp-1 and timp-1 levels in patients with various inflammatory arthritides
Authors: S Pay, H Erdem, M Serdar, A Dinc, I Simsek, M Turan
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Some inflammatory arthritides like a rheumatoid arthritis cause erosion in bones and destruction in cartilage, but others such as Behçet's Disease (BD) and Familial Mediterranean Fever (FMF) do not. <h3>Objectives</h3> The purpose of this study was to investigate synovial levels of matrix metalloproteinase ?1 (MMP-1) known to break collagen, and tissue inhibitor of metalloproteinase (TIMP-1), its natural antagonist, in patients with various inflammatory disorders. <h3>Methods</h3> One hundred and nine patients with different inflammatory arthritides were enrolled in the study (20 BD, 20 FMF, 24 spondyloarthropathy (SPA), 26 rheumatoid arthritis (RA) and 19 osteoarthritis (OA)). All patients had at least one-sided knee arthritis from which synovial fluid samples were obtained. Patients with BD, FMF and SPA constituted three study groups. Patients with RA and OA were used as control groups. Synovial MMP-1 and TIMP-1 levels were measured by two-step sandwich ELISA. <h3>Results</h3> The mean levels of synovial MMP-1 and TIMP-1 of the study and control groups presented in Table 1. <h3>Conclusion</h3> Although FMF and BD are generally characterised by nonerosive arthritis, our results showed that synovial MMP-1 levels of patients with BD and FMF were not different from the patients with RA, which is a well-known erosive arthritis. We suggested two possible explanations for these unexpected data. First, BD and FMF generally cause short term arthritic attacks, remitting without permanent damage. Second, high synovial MMP-1 levels in BD and FMF may be resulted from extra articular origin, because of their systemic nature. The comparison of synovial MMP-1 levels between RA and SPA was statistically significant. This may help to explain why SPA causes less prominent destruction in cartilages and erosion in bones than RA. Except OA, the difference between the groups with respect to the synovial TIMP-1 levels was statistically insignificant.