tbuckley/cabot-search huggingface dataset:
Abstract 15673: CRISPR-Cas9 Gene Editing in Mice Reveals Novel Thrombotic Function of a Human SNP in STXBP5
Authors: Qiuyu Zhu, Kyung Ae Ko, Sara Ture, Craig N Morrell, Joseph M Miano, Charles J Lowenstein
Journal: Circulation (2015)

Introduction: Endothelial cells responds to vascular injury by exocytosis, releasing von Willebrand factor (vWF) into the blood stream. However, the regulation of endothelial vWF release remains poorly understood. Recent genome-wide association studies (GWAS) have identified syntaxin-binding protein 5 (STXBP5) as a candidate gene linked to changes in vWF plasma levels. One top nonsynonymous single nucleotide polymorphism (SNP), rs1039084 (hg19 chr6:g.147635413A&gt;G), encodes p. Asn436Ser substitution (STXBP5-N436S), and is associated with lower plasma vWF, higher bleeding score, and decreased venous thrombosis in humans. We recently discovered that STXBP5 inhibits endothelial vWF exocytosis and regulates thrombosis. However, the role of the STXBP5 genetic variants linked to vWF levels are not completely understood. Hypothesis: We hypothesized that STXBP5-N436S further inhibits endothelial exocytosis than wild type (STXBP5-WT). Methods: We overexpressed STXBP5-WT and STXBP5-N436S in cultured human endothelial cells and measured VWF release changes. Using CRISPR-Cas9 technique, we generated mice carrying the human rs1039084 SNP in Stxbp5 locus (Stxbp5-N437S mice). We conducted phenotypic analyses including endothelial exocytosis, hemostasis, and thrombosis in wild-type and Stxbp5-N437S mice. Results: In human endothelial cells, overexpression of STXBP5-N436S inhibits vWF exocytosis more potently than STXBP5-WT. Germline CRISPR-Cas9 gene editing efficiently and precisely knocked-in the human rs1039084 SNP in murine Stxbp5 locus, without causing detectable off-target genome cleavage. The baseline plasma vWF levels of Stxbp5-N437S mice are similar to WT mice, but Stxbp5-N437S mice showed impaired vWF exocytosis in response to epinephrine challenge. Moreover, Stxbp5-N437S mice have severe hemostasis defects displayed as prolonged bleeding time. Finally, Stxbp5-N437S mice have impaired mesenteric vessel thrombosis and carotid artery thrombosis. We are now studying the effects of the SNP upon STXBP5 structure and function. Conclusions: Our study validates the functional relevance of a candidate SNP identified by GWAS, and suggests that genetic variations within STXBP5 is a risk factor for thromboembolic disease.
EXTH-75. THE AURORA KINASE A INHIBITOR ALISERTIB IS SYNERGISTIC WITH IRINOTECAN AND CARBOPLATIN AGAINST GLIOBLASTOMA CELLS
Authors: Eric Burton, Cory Zumbar, Paul King, Muge Sak, Aisulu Usubalieva, Xiaohui Li, Caroline Mifsud, Joseph McElroy, Norman Lehman
Journal: Neuro-Oncology (2018)

Alisertib is a selective AURKA inhibitor currently in clinical trial for recurrent glioblastoma. We have previously shown that alisertib potently inhibits growth of glioblastoma cells in vitro and in vivo. As effective chemotherapeutic approaches for refractory glioblastoma may require a combination of agents, we tested the efficacy of alisertib to potentiate the effects of carboplatin and irinotecan. The ability of alisertib to potentiate the growth inhibitory effects of these agents was assessed by using colony formation assays with cultured glioblastoma cells. Alisertib potentiated the anti-proliferative action of both irinotecan and carboplatin in these assays. This effect was often synergistic, including against glioblastoma tumor stem-like cells (neurospheres), as demonstrated by Chou-Talalay and Bliss analyses. We then compared O6-methylguanine DNA methyltransferase (MGMT) expression levels of each cell line by western blotting, and found that high MGMT expression correlated with more pronounced potentiation of carboplatin’s growth inhibitory effects by alisertib, while low MGMT expression correlated with stronger potentiation of irinotecan by alisertib. This suggests that MGMT expression levels may be predictive of patient response to these drug combinations, however additional studies are required to confirm this possibility. Since clinical experience with alisertib, carboplatin and irinotecan as single agents already exists, these findings may provide rationale for the design of clinical trials for their use in combination treatment regimens.
CMET-12. DISTANT BRAIN FAILURE FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES FROM BREAST CANCER
Authors: Andrew Keller, Sean All, Hanisha Patel, Steven Nguyen, Luke Pearson, Naren Ramakrishna
Journal: Neuro-Oncology (2018)

Leptomeningeal spread of cancer can have protean presentations, increasing the difficulty of making this diagnosis.We present the case of a 77-year-old man with prior metastatic melanoma who presented with spontaneous headache that worsened over several days, and was found to have both intraventricular and cortical subarachnoid hemorrhage on CT head.His neurological exam was unremarkable.MRI of the brain with contrast confirmed the CT findings and did not reveal any evidence of parenchymal or leptomeningeal metastases.MR angiogram followed by a conventional angiogram did not demonstrate any vascular abnormalities.Cerebrospinal fluid examination revealed 110 white blood cells, 34000 red blood cells, and protein of 160.Cytology returned positive for malignant melanoma cells.No additional sites of disease were found on further evaluation with MRI spine and CT of the chest, abdomen and pelvis.In retrospect, the patient had endorsed some fluctuating nausea and fatigue three months prior to presentation, as well as positional vertigo two weeks prior to presentation.His oncologic history was notable for prior immunotherapy with ipilimumab, as well as diagnosis of dural-based brain metastases two years earlier, for which he underwent surgical resection and radiation therapy.He had no evidence of disease for one year prior to this new diagnosis of leptomeningeal involvement.This case highlights an unusual presentation of leptomeningeal metastasis and underscores the importance of maintaining heightened suspicion for this diagnosis when evaluating subarachnoid hemorrhage in a cancer patient, especially in the case of melanoma.It raises the question of whether this particular cancer type or the patient's prior immunotherapy contributed to his presentation, and emphasizes the need for further elucidation of the biology of leptomeningeal metastasis.
Abstract 18838: An Endogenous Tetrapeptide N-acetyl-Ser-Asp-Lys-Pro Inhibits Radiation-Induced Myocardial Inflammation and Fibrosis
Authors: Umesh Sharma, Swati Sonkawade, Suraj Dahal, Coral Sanchez-Malave, Joseph Spernyak, Anurag Singh, Saraswati Pokharel
Journal: Circulation (2017)

Introduction: Radiotherapy (RT) is a commonly used adjuvant therapy for thoracic cancers. However, radiation exposure also induces myocardial inflammation and fibrosis. No therapy is currently available to antagonize these effects. Hypothesis: We tested the hypothesis that a novel tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) counteracts radiation-induced myocardial inflammation and fibrosis. Such protective effects of Ac-SDKP are exerted by inhibiting a pro-inflammatory and pro-fibrotic mediator, galectin-3. Methods: We generated a rat model of cardiac inflammation and fibrosis by using external beam radiation (30Gy, single-dose). Post radiation, we treated these rats with continuous Ac-SDKP infusion and measured their cardiac function using 4.7T cardiac MRI. On completion of Ac-SDKP therapy, we quantified cardiac fibrosis by trichrome staining, macrophage infiltration by CD68 immunostaining and galectin-3 expression by enzyme-linked immunoassays. We also localized Ac-SDKP binding sites into macrophage...
M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer
Authors: Jingqin Lan, Li Sun, Feng Xu, Lu Liu, Fuqing Hu, Da Song, Zhenlin Hou, Wei Wu, Xuelai Luo, Jing Wang, Xianglin Yuan, Junbo Hu, Guihua Wang
Journal: Cancer Research (2018)

Clinical and experimental evidence has shown that tumor-associated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer metastasis have not been fully characterized. Here, we demonstrate that M2 macrophage-regulated colorectal cancer cells' migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated colorectal cancer cells' migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to colorectal cancer cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting the colorectal cancer metastasis, yet is downregulated in metastatic colorectal cancer cells. Collectively, these findings show that M2 macrophages induce colorectal cancer cells' migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between colorectal cancer cells and M2 macrophages provides a new opportunity for the treatment of metastatic colorectal cancer. SIGNIFICANCE: These findings report a functional role for miRNA-containing exosomes derived from M2 macrophages in regulating migration and invasion of colorectal cancer cells.
2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay
Authors: Fred M. Kusumoto, Mark H. Schoenfeld, Coletta Barrett, James R. Edgerton, Kenneth A. Ellenbogen, Michael R. Gold, Nora F. Goldschlager, Robert M. Hamilton, José A. Joglar, Robert J. Kim, Richard Lee, Joseph E. Marine, Christopher J. McLeod, Keith R. Oken, Kristen K. Patton, Cara N. Pellegrini, Kimberly A. Selzman, Annemarie Thompson, Paul D. Varosy
Journal: Journal of the American College of Cardiology (2018)
Role Models, Allies, and Diversity—Global Issues for Female Cardiology Trainees—Reply
Authors: Pamela S. Douglas
Journal: JAMA Cardiology (2018)

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Endoscopic treatment or balloon-occluded retrograde transvenous obliteration is safe for patients with esophageal/gastric varices in Child-Pugh class C end-stage liver cirrhosis
Authors: Keiji Yokoyama, Ryo Yamauchi, Kumiko Shibata, Hiromi Fukuda, Hideo Kunimoto, Kazuhide Takata, Takashi Tanaka, Shinjiro Inomata, Daisuke Morihara, Yasuaki Takeyama, Satoshi Shakado, Shotaro Sakisaka
Journal: Clinical and Molecular Hepatology (2018)

See the commentary-article "Role of endoscopic treatment or balloon-occluded retrograde transvenous obliteration in patients with Child-Pugh class C end-stage liver cirrhosis and esophageal/gastric varices" on page 181.
TMOD-22. MODELING SEX DIFFERENCES IN p53 GAIN-OF-FUNCTION MUTATIONS IN GLIOBLASTOMA
Authors: Nathan Rockwell, Nicole Warrington, Joshua Rubin
Journal: Neuro-Oncology (2018)

The tumor suppressor TP53 (p53) is the most commonly mutated gene in cancer and is one of the most frequently mutated genes in glioblastoma (GBM). The most common p53 mutations are missense mutations in the DNA binding domain that lead to the expression of full length mutant p53 protein. In addition to the loss of tumor suppressor function, these mutations can endow oncogenic gain-of-function abilities that allow mutant p53 to bind and regulate the promoters of aberrant target genes, driving tumorigenesis. However, the mechanisms that control mutant p53 target gene specificity and the subsequent malignant phenotypes are poorly understood. We combined and analyzed patient mutation data from the COSMIC, TCGA and IARC databases to determine the prevalence of individual p53 mutations in CNS tumors. This revealed a subset of six missense mutations that exhibit significant sex differences in their frequency, suggesting that these mutations may have a sex specific effect on cancer cell fitness. Four codons were mutated more frequently in females: Y205 (p=0.004), D184 (p=0.0172), V216 (p=0.0253), and V272 (p=0.0336), and two codons were mutated more frequently in males: Y220 (p=0.0104) and R282 (p=0.0496). We developed a murine astrocyte model that will allow us to investigate the sex specific effect of each gain-of-function mutation on transcription and tumorigenesis. Using CRISPR/Cas9, relevant point mutations were inserted into the p53 DNA-binding-domain of male and female p53 heterozygous primary mouse astrocytes. These astrocytes express a single mutant p53 allele, and reflect the silencing of the WT p53 allele common in GBM. Using this model, we can directly compare the transcriptional activity of each gain-of-function mutation using ChIP-sequencing and RNA-sequencing. These cells also provide a unique model for mechanistic studies to determine the tumorigenic effects of each gain-of-function mutation, including proliferation, invasion, clonogenicity and in vivo tumorigenesis.
RDNA-02. TUMOR TREATING FIELDS DIFFERENTIALLY ALTER HOMOLOGOUS RECOMBINATION IN PATIENT DERIVED GLIOMA CELLS VERSUS ESTABLISHED LINES
Authors: Lawrence Bronk, Ravesanker Ezhilarasan, Yingwen Ding, Ze-yan Zhang, Erik Sulman
Journal: Neuro-Oncology (2018)

Within the heterogeneous tumor cell population there exists a subpopulation exhibiting stem-like properties known as glioma stem cells(GSCs) which are thought to be prime contributors in tumor resilience. Low-frequency alternating electric fields, tumor treating fields(TTFs), have recently emerged as a novel form of radiotherapy with FDA approval for the treatment of glioblastoma. We sought to determine the anti-proliferative effects of TTFs using a panel of 4 patient-derived GSCs and established lines, U87 and U373. Using the Novocure Inovitro system, cells were treated with 200kHz TTFs for 72hr and the cell number was determined using a Vi-Cell Cell Viability Analyzer. We found a statistically significant reduction in cell growth following TTF exposure for 4 of the 6 cell lines tested. The size of the anti-proliferative effect was cell line dependent and varied between 15 and 30%. We examined the effect of TTFs on the DNA damage response following irradiation utilizing immunofluorescent foci staining kinetics coupled with high-throughput automated imaging and analysis. Our initial results demonstrated a varied response among the tested cell lines. A 48hr TTF application increased the number of 53bp1 foci above background in U87 and two of the tested GSCs. TTF application for 24hr prior to irradiation was found to systematically reduce the number of induced Rad51 repair foci. However, an increased number of persistent Rad51 foci in the established lines was measured, indicative of reduced repair. In contrast, within the GSCs, the initial reduction in Rad51 foci was maintained throughout the 24hr repair time course. Our preliminary results have demonstrated the efficacy of TTFs to reduce cancerous cell proliferation in vitro while uncovering a differential DNA damage modulation response between established lines and GSCs. Future studies will focus on elucidating the mechanism of GSC TTF resistance with the goal of increasing treatment efficacy via multi-modal combination therapy.
HOUT-01. A RETROSPECTIVE ANALYSIS OF OUTCOMES WITH TEMOZOLOMIDE AS INITIAL TREATMENT OF GRADE 2 OLIGODENDROGLIOMA
Authors: Hollie Morales, Lauren Homer, Jordan Langford, Amiee Maxwell, Matthew Smith-Cohn, Randy Jensen, Howard Colman, Adam Cohen
Journal: Neuro-Oncology (2018)

Prior randomized studies have shown a survival benefit of radiation and chemotherapy compared to radiation alone for grade 2 gliomas (astrocytoma and oligodendroglioma) and grade 3 oligodendroglioma. However, data is mixed regarding outcomes for patients treated initially with chemotherapy alone as well as outcomes based on sequence of chemotherapy and radiation treatments. We performed a retrospective analysis of outcomes in grade 2 oligodendroglioma treated initially with temozolomide (TMZ) alone. Variables included in the analysis were age, extent of resection, timing of TMZ treatment, progression free survival, and overall survival. A total of 37 patients with grade 2 oligodendroglioma who received TMZ as the first course of treatment were identified. Median age at diagnosis was 43 years. Extent of resection was as follows: complete resection 32%, subtotal resection 43%, stereotactic biopsy 14%, and unknown in 11%. Of the 37 patients in the cohort, 41% received TMZ immediately following initial diagnosis with the remaining 59% receiving TMZ after initial observation. Median PFS after TMZ treatment was 3.94 years, and 25% of patients treated with TMZ alone progressed within 2 years. Despite the high rate of early progressors, the median overall survival with TMZ alone as initial treatment was 15.46 years Extent of resection was not significantly associated with survival. This retrospective series supports the observations from the TMZ monotherapy exploratory arm of CODEL that PFS in oligodendroglioma patients treated with TMZ alone as initial therapy is likely significantly worse than patients treated with combination of radiation and chemotherapy. The relatively good OS in this same patient population suggests that additional salvage therapy at the time of progression may still result in prolonged survival. Clinical and molecular biomarkers are needed to identify higher or lower risk subtypes within oligodendrogliomas to assist in treatment decision making.
DDIS-26. BTP-7, A NOVEL PEPTIDE FOR THERAPEUTIC TARGETING OF MALIGNANT BRAIN TUMORS
Authors: Choi-Fong Cho, Yarah Ghotmi, Colin Fadzan, Justin Wolfe, Sonja Bergmann, Yuan Qu, Emily Murrell, Fernanda Bononi, Leonard Luyt, E Antonio Chiocca, Mariano Viapiano, Bradley Pentelute, Sean Lawler
Journal: Neuro-Oncology (2018)

High-grade gliomas are deadly cancers, and current standard-of-care has demonstrated limited success. The ability to specifically target glioma cells can allow for the development of safer and more efficacious brain cancer therapy strategies. Brevican, a CNS-specific extracellular matrix protein is upregulated in glioma cells and its expression correlates with tumor progression. Particularly, a brevican isoform lacking glycosylation, B/bΔg is a unique glioma marker and not expressed in non-cancerous tissues. Therefore, B/bΔg represents a valuable target for anti-cancer strategies. Here, we describe the utilization of state-of-the-art platforms to screen a one-bead-one-compound combinatorial peptide library to discover a novel "B/bΔg-Targeting Peptides", called BTP-7 that can bind B/bΔg with high affinity and specificity. BTP-7 displayed 260 nanomolar affinity for recombinant B/bΔg protein, and had little association with the fully glycosylated isoform of brevican (control). Scrambling of the BTP-7 sequence led to complete abrogation of B/bΔg binding. Furthermore, BTP-7 is preferentially taken up by B/bΔg-expressing glioma cells compared with non-expressing cells. We also discovered that BTP-7 can cross the blood-brain barrier using both the in vitro BBB organoid model and in mice. BTP-7 displayed 10x greater binding to intracranial GBM-6 tumors than control peptides, and 4x higher tumor uptake than in normal brain tissues. Conjugation of BTP-7 to camptothecin (an anti-tumor drug) via a cleavable linker led to increased DNA damage in intracranial GBM-6 tumors and prolonged survival in tumor-bearing mice. Our results show the potential of BTP-7 for the development of next-generation targeted therapeutics that could greatly benefit the outcome of patients with advanced brain cancer.
Abstract 17523: Incidence of Atrial Fibrillation and Relation with Cardiovascular Events, Heart Failure and Mortality in a European Community-Based Study - Data of PREVEND
Authors: Rob A Vermond, Bastiaan Geelhoed, Niek Verweij, Robert G Tieleman, Pim Van der Harst, Hans L Hillege, Wiek H Van Gilst, Isabelle C Van Gelder, Michiel Rienstra
Journal: Circulation (2014)

Objectives: We investigate the incidence of atrial fibrillation (AF), risk factors of incident AF, and associations with cardiovascular events, systolic and diastolic heart failure and all cause mo...
RBTT-08. A RANDOMIZED PHASE 2 OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VERSUS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (GBM)
Authors: Manmeet Ahluwalia, Jaleh Fallah, David Peereboom, Cathy Schilero, Assad Ali, Deborah Forst, Eric Wong, Patrick Wen, David Reardon
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Initial trials with anti-PD1 in recurrent glioblastoma showed limited efficacy. Vascular endothelial growth factor (VEGF) is a highly upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression by inhibition of dendritic cell maturation and antigen presentation, induction of apoptosis of CD8+ T-cells and enhancing Treg activity. Hence, a combination of anti-PD1 and anti-VEGF is promising approach in recurrent GBM. METHOD This is a 90 patient randomized, open-label, phase 2 safety study of Nivolumab and bevacizumab administered according to standard and reduced dosage schedules in patients with first recurrence of GBM. Patients will undergo 1:1 randomization to receive treatment with either Nivolumab (240 mg flat dosing IV every 2 weeks) and bevacizumab administered according to standard (10 mg/kg IV every 2 weeks; Arm A) and reduced (3 mg/kg IV every 2 weeks; Arm B) dosage schedules for recurrent glioblastoma patients. The study will allow patients that require dexamethasone up to 4 mg/day to participate in the study. All subjects will be followed for safety and tolerability, tumor progression and overall survival. Tumor progression or response endpoints will be assessed using the Radiologic Assessment in Neuro-Oncology (RANO) criteria and an exploratory endpoint will evaluate the response endpoints using the Immunotherapy RANO (iRANO). Treatment with study medication will continue until confirmed tumor progression, unacceptable toxicity or death. It is expected that enrollment and follow-up of randomized subjects (45 subjects in each arm) will take approximately 12months. The one-sample log-rank test will be applied to outcomes observed for each arm individually to test the hypothesis that OS has been improved beyond the null 12-month survival rate of 45%. With N=45 patients per arm, a one-sided test provides power=0.80 to detect survival rate of 58% at 12-months following treatment at the 0.10 significance level. The study (NCT03452579) is ongoing and enrolling patients.
Abstract 15700: Modified Human Mesenchymal Stromal Cells (MSCs) Improve Glucose Homeostasis in Diet induced Obese (DIO) Diabetic Mouse Model
Authors: Cleyton C Domingues, Nabanita Kundu, Neeki Ahmadi, Sabyasachi Sen
Journal: Circulation (2016)

Background: MSCs are undifferentiated, multipotent cells. We have previously showed that High Glucose (HG, 25mM) exposure promotes adipogenic differentiation, MSC inflammation, increased formation ...