tbuckley/cabot-search huggingface dataset:
NIMG-25. TRANSFERRIN RECEPTOR 1 TARGETED PET/CT AND NIFR PROBES FOR IMAGING GLIOBLASTOMA MOUSE MODELS
Authors: Xiang-Rong Ni, Yi-Ying Zhao, Hai-Ping Cai, Zhi-Hui Yu, Jing Wang, Fu-Rong Chen, Yan-Jiao Yu, Guo-Kai Feng, Zhong-ping chen
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE A new imaging technology that indiscriminately detects intracranial glioblastoma (GBM) can help neurosurgeons remove tumor mass completely. Transferrin receptors (TfR 1) have been widely investigated as a diagnostic and therapeutic target in GBM. A TfR 1-targeted peptide, CRTIGPSVC (CRT) can accumulate at high levels in GBM tissues. In our study, taking the advantage of CRT, we synthesized two molecular imaging probes for imaging GBM precisely. One is a PET/CT probe 18F-NOTA-CRT, and the other is a near-infrared fluorescent (NIFR) probe Cy5-CRT. METHODS We initially confirmed the overexpression of TfR 1 in most of GBM and the tumor-specific homing ability of 18F-NOTA-CRT and Cy5-CRT in orthotopic U87 GBM (TfR 1 overexpression) mouse models. We then examined the feasibility of Cy5-CRT for specially identifying the GBM tissue margin in the intracranial U87 xenografts in vivo and ex vivo. Next, we compared Cy5-CRT with the clinically used fluorescein sodium in identifying tumor margins. Finally, we used Cy5-CRT to carry out a fluorescence-guided operation on a orthotopic U87 mouse model. RESULTS Both 18F-NOTA-CRT and Cy5-CRT probes specifically accumulated in U87 GBM xenografts with TfR 1 overexpression, but not in U373 GBM xenografts with very low TfR 1 expression. Cy5-CRT detected the intracranial tumor burden with exceptional contrast, enabling fluorescence-guided GBM resection under NIFR live imaging conditions. Importantly, Cy5-CRT recognized the GBM tissue margin more clearly than fluorescein sodium. CONCLUSIONS Our probes were capable of thoroughly detecting GBM tissue in vivo imaging. For translational applications, we may screen patients before surgery by PET/CT imaging with 18F-NOTA-CRT to identify gliomas with TfR 1 overexpression. As for fluorescence-guided surgery, the TfR 1-targeted optical probe Cy5-CRT specifically differentiates tumor tissues from normal brain with high sensitivity, indicating its potential application for the precise surgical removal of GBM. Keywords: Transferrin receptor 1; PET/CT; near-infrared fluorescence imaging; glioblastoma, fluorescence-guided surgery
Abstract 16013: Systolic Blood Pressure and Mortality in Patients With Diabetes and Heart Failure: A Population-Based Cohort Study
Authors: Abi Khalil Charbel, Omar Omar, Jassim Al Suwaidi, Shahrad Taheri
Journal: Circulation (2018)

Introduction: The ideal systolic blood pressure (SBP) in patients with type 2 diabetes (T2D) and heart failure (HF) is not known. Hypothesis: Wehypothesized that SBP is has a J-shape relation with ...
DIPG-76. HISTONE H3 PHOSPHORYLATION IN H3K27M MIDLINE GLIOMAS
Authors: Liang Zhang, Charles Day, Edward Hinchcliffe, David Daniels
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas (DMG) patients have a dire prognosis despite radiation therapy and there is an urgent need to develop more effective treatments. DMG are characterized by heterozygous mutations in select H3 genes resulting in the replacement of lysine 27 by methionine (K27M) that leads to global epigenetic reprogramming and drives tumorigenesis. We previously reported that pharmacological inhibition of aurora kinase (AKI) may represent a targeted approach for treating tumors with this mutation. Our analysis with both published dataset and patient samples showed that patients with higher aurora kinase A (AKA) expression were associated with worse survival. AKA phosphorylates H3S10 and H3S28 during mitosis. Intriguingly, phosphorylation of the H3S28 (H3S28ph) by AKA blocks PRC2 methyltransferase activity and decreases global H3K27me3 in certain stem cells. We propose that a similar mechanism occurs in H3K27M DMG tumors, where there is a reciprocal relationship between H3S28ph and H3K27me3. We found that AKI significantly decreases H3S28ph while increasing H3K27me3 specifically in H3K27M tumors. To further evaluate the link between the H3K27M mutation and H3 serine phosphorylation, we used CRISPR/Cas9-directed gene editing to silence H3S28ph by replacing serine with alanine (H3S28A) in DIPG cell lines. Ectopic expression of histone H3S28A leads to a prominent epigenetic changes in H3K27M tumors and is similar to AKA inhibition. Overall, this study highlights H3S28ph, one of the targets of AK, is a key driver of epigenetic changes in H3K27M tumors through both direct and indirect changes to H3K27me3 and H3K27ac across the genome.
CTIM-27. PHASE I/II STUDY OF CONTROLLED IL-12 AS IMMUNOTHERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Stewart Goldman, Sabine Mueller, Susan Chi, Amanda Saratsis, Rudy Allen, Jill Buck, Nathan Demars, Nira Hadar, Taylor Estupinan, John Miao, Erin Walsh, Arnold Gelb, Laurence Cooper
Journal: Neuro-Oncology (2020)

Abstract DIPG, which is the leading cause of pediatric brain cancer death with no effective treatment, has neither a highly immunosuppressive nor inflammatory tumor microenvironment (TME). Therefore, eliciting a pro-inflammatory TME may provide therapeutic benefit. We previously demonstrated in adults with recurrent glioblastoma that loco-regional delivery of interleukin 12 administered under the control of the proprietary transcriptional switch RheoSwitch Therapeutic Systemâ (RTSâ) delivered via a replication-incompetent adenovirus (“Controlled IL-12”) turned “cold” tumors “hot” for up to 5.8 months (Sci Transl Med. 2019;11(505)) and seemed to improve median overall survival as compared with historical controls (SNO 2020). A multicenter, phase I/II, open-label study (NCT03330197) is determining the safety and tolerability of Ad (2 x 1011 viral particles) administered by stereotactic intratumoral injection (Day 0) and 14 daily (Days 1 to 14) V doses (10 or 20 mg, body surface area adjusted). The first DIPG subject enrolled was in April 2020 with completion of the first cohort (arm 1, n=3) enrollment anticipated by September 2020. The first subject has tolerated treatment well with no SAEs during the evaluation period. Endogenous serum cytokines increased (including IFN-g 11.4 pg/mL, Day 3), consistent with V crossing the blood-brain barrier and activating the RTSâ switch to conditionally produce recombinant IL-12. Other biomarkers include plasma PK and circulating DNA. Follow-up is ongoing and enrollment is proceeding. Since development of effective immunotherapy for DIPG likely depends on eliciting a tumor-specific effector immune response, Controlled IL-12 is a promising immunotherapy candidate. The first DIPG subject shows encouraging data on safety, tolerability, serum cytokines and early signs consistent with a clinical response. After completion of dose-escalation, the study may be expanded up to 30 patients, which will be considered the phase II component of the study.
MBRS-42. YB-1 - A NOVEL THERAPEUTIC TARGET IN HIGH-RISK MEDULLOBLASTOMA?
Authors: Louisa Taylor, Ian Kerr, Beth Coyle
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma relapse occurs in 30–40% of patients and is typically fatal. The emergence of therapy resistant sub-clones likely plays a major role in a large proportion of recurrent medulloblastoma. Y-box binding protein 1 (YB-1) is a multifunctional transcription/translation factor and known onco-protein. Overexpression has been described in numerous cancers, where elevated expression and nuclear accumulation correlates with disease progression, metastasis and drug resistance. Genomic analysis of a large medulloblastoma cohort revealed YB-1 up-regulation across all subgroups of medulloblastoma, where elevated expression correlated with poor survival. Immunohistochemical staining of patient tissue microarrays displayed significant YB-1 expression, with a high proportion (83%) of patients exhibiting nuclear accumulation. High YB-1 expression was also observed at both protein and RNA level across medulloblastoma cell lines, with expression highest in Group 3 and 4. Hence, we hypothesised that YB-1 plays a role in medulloblastoma chemoresistance and progression. Treatment of Group 3 (HDMB-03 and D283MED) and SHH (DAOY) cell lines with vincristine and cisplatin and analysis of cellular localisation by nuclear/cytoplasmic fractionation and immunofluorescence demonstrated that YB-1 undergoes nuclear translocation in response to these standard medulloblastoma chemotherapy agents. Chromatin immunoprecipitation (ChIP) analysis of untreated Group 3 cell lines (D283MED and HDMB-03) demonstrated considerable YB-1 interaction with an inverted CCAAT box in the ATP-binding cassette subfamily B member 1 (ABCB1) promoter. RT-PCR analysis of ABCB1 following vincristine and cisplatin treatment revealed differences in transcript expression, indicative of different YB-1 promoter interactions dependent on chemotherapeutic treatment. Our results highlight YB-1 as a novel candidate chemoresistance driver in medulloblastoma.
Association of Political Party Affiliation With Physical Distancing Among Young Adults During the COVID-19 Pandemic
Authors: Adam M. Leventhal, Hongying Dai, Jessica L. Barrington-Trimis, Rob McConnell, Jennifer B. Unger, Steve Sussman, Junhan Cho
Journal: JAMA Internal Medicine (2020)

Public messages about physical distancing during the coronavirus disease 2019 (COVID-19) pandemic in the US have diverged across government officials and news media outlets with different political leanings. 1 Prior studies found that people with Republican (vs other) political party affiliations report less physical distancing. 2,3 These studies used crowdsourced internet samples, inadequately adjusted for confounders, collected data before widespread public health messaging about physical distancing, or included few young adults. 2,3 Adults aged 18 to 25 years might be inclined to contravene physical distancing guidelines and participate in highrisk social recreational activities that increase the risk of transmitting severe acute respiratory syndrome coronavirus 2. 3 We estimated the associations of political party affiliation with physical distancing behaviors among young adults-a population with high rates of COVID-19. 4 Methods | Ninth grade high school students (n = 3396) were originally recruited in Los Angeles, California, in 2013, provided informed written consent, and were surveyed (semi) annually about health behaviors. 5 This cross-sectional study analyzed self-report data from the most recent (May 18-August 3, 2020) survey administered online.The University of Southern California institutional review board approved the study.Written informed consent was obtained and the survey responses were analyzed in a deidentified data set.A political party affiliation survey item with 6 response options was collapsed into 4 categories ("Democrat," "Republican," "Independent," "something else," "don't know" or "prefer not to answer").Physical distancing (defined as staying ≥6 feet away from others) over the past 2 weeks with 5 response options was made a binary outcome (infrequent ["sometimes" or "rarely"] vs frequent ["usually," "always," or "not been in public places"]).Past 2-week frequency of engaging in 4 social recreational activities (listed in Table 1) was measured.Responses to the 4 items ("0," "1," "2-3" [recoded = 2.5], "4-6" [recoded = 5], or "≥7" [recoded = 7] times) were summed into a continuous outcome (range: 0-28) and examined individually as binary outcomes (≥1 vs 0 times).
MODL-21. INTEGRATIVE APPROACHES IN FUNCTIONAL GENOMICS TO IDENTIFY GENETIC DEPENDENCIES IN PEDIATRIC BRAIN CANCER
Authors: Claire Sun, Caroline Drinkwater, Dhanya Sooraj, Gabrielle Bradshaw, Claire Shi, Dasun Fernando, Sarah Parackal, Daniel Gough, Jason Cain, Ron Firestein
Journal: Neuro-Oncology (2020)

Abstract The precise decoding of human genomes facilitated by the advancements in next-generation sequencing has led to a better understanding of genetic underpinnings of pediatric brain cancers. Indeed, it is now evident that tumours of the same type harbour distinct driving mutations and molecular aberrations that can result in different prognosis and treatment outcomes. The profounder insight into the the identity, amount and types of molecular aberrations has paved the way for the advent of targeted therapies in precision medicine. Nevertheless, less than 10% of pediatric cancer patients harbour actionable mutations. Strictly limited therapeutic options that are firstly available for brain cancers and secondly acceptable for children’s development further impede the breakthrough in the survival rate in pediatric brain cancers. This underscores a desperate need to delve beyond genomic sequencing to identify biomarker coupled therapies that not only featured with treatment efficacy in the central nervous system but also acceptable side effects for children. The Hudson-Monash Paediatric Precision Medicine (HMPPM) Program focuses on utilising genetic profiles of patients’ tumour models to identify new therapeutic targets and repurpose existing ones using high-throughput functional genomics screens (2220 drugs and CRISPR screen of 300 oncogenic genes). Using a large compendium of over sixty patient derived paediatric brain cancer models, we provide proof-of-concept data that shows an integrative pipeline for functional genomics with multi-omics datasets to perform genotype-phenotype correlations and, therefore, identify genetic dependencies. Herein, using several examples in ATRT, DIPG and HGG, we show how functional interrogations can better define molecular subclassification of tumours and identify unique vulnerabilities.
Rare cause of emphysema
Authors: Tobias Matthieu Benoit, Rahel Schwotzer, Didier Schneiter, Jan Hendrik Rüschoff, Daniel Peter Franzen
Journal: Thorax (2020)

A 52-year-old man with chronic obstructive pulmonary disease GOLD 4, group D, and severe, heterogeneous pulmonary emphysema (figure 1) and marked hyperinflation was treated with bronchoscopic lung volume reduction (LVR) using endobronchial valves (EBVs) and, 6 months thereafter, bilateral thoracoscopic lung volume reduction surgery (LVRS), both after multidisciplinary team consensus. The interventions individually resulted in a clear but only short-term success due to rapid progression of emphysema and hyperinflation. After EBV treatment, forced expiratory volume in one second (FEV1) improved from 0.86 L (23% predicted) to 1.16 L (31% predicted), and residual volume (RV) improved from 5.14 L (219% predicted) to 4.93 L (210%). Only 4 months thereafter, FEV1 dropped to 0.68 L (18%), while RV increased to 5.84 L (266% predicted). At 3 months after LVRS, FEV1 increased again to 0.87 L (23% predicted), and RV decreased to 5.40 L (227% predicted). However, chest CT revealed progressive emphysematous changes, and the patient experienced increasing dyspnoea again. Negligible …
EXTH-43. GENERATION OF A B-CELL-BASED VACCINE FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Catalina Lee Chang, Jason Miska, David Hou, Aida Rashidi, Peng Zhang, Rachel Burga, Ignacio Jusue Torres, Ting Xiao, Victor Arrieta, Daniel Zhang, Aurora Lopez-Rosas, Yu Han, Adam Sonabend, Craig Horbinski, Roger Stupp, Irina Balyasnikova, Maciej Lesniak
Journal: Neuro-Oncology (2020)

Abstract Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNg stimulation. BVaxmigrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice. GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce tumor-specific antibodies able to control tumor growth via antibody-mediated cell cytotoxicity. In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.
CMV Status Predicts Survival in Refractory/Relapsed Myeloid Patients after a Clofarabine-Based Sequential Regimen: A Retrospective Study on Behalf of the SFGM-TC
Authors: Amandine Le Bourgeois, Myriam Labopin, Felipe Suarez, Regis Peffault De Latour, Didier Blaise, Sylvain Chantepie, Stephanie Nguyen-Quoc, Natacha Maillard, Reza Tabrizi, Ibrahim Yakoub-Agha, Anne Huynh, Tony Marchand, Karin Bilger, Patrice Ceballos, Amandine Charbonnier, Pascal Turlure, Mohamad Mohty, Patrice Chevallier
Journal: Blood (2017)
OTHR-14. DIENCEPHALIC SYNDROME SECONDARY TO PITUITARY STALK THICKENING
Authors: Carlos Almeida, Bruna Minniti Mançano, Gilda D’Agostino Eugui, Marcus Matsushita, Gabrielle Alvarenga, Lucas Dias Lourenço
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diencephalic syndrome (DS) is a rare condition associated with neoplastic lesions of the sellar-suprasellar region, whose pathophysiological mechanisms are still unclear. DS occurs in &amp;lt;10% of hypothalamic gliomas and has also been described in suprasellar germinomas, craniopharyngiomas, epidermoid cysts, rarely with non-suprasellar lesions such as brainstem gliomas. DS has not been associated with isolated pituitary stalk thickening. Isolated pituitary stalk thickening (IPST) presents a diagnostic challenge, ranging from benign (craniopharyngioma) to malignant lesions (germinoma, metastasis, histiocytoses of the Langerhans group). The coexistence of diabetes insipidus (DI) with anterior pituitary dysfunction and IPST implies more risk to harbor neoplasia. CASE REPORT: A 6-year old girl presented with DI and inadequate weight gain (despite regular caloric intake) and preservation of linear growth. Neurological examination showed no abnormalities. However, physical examination revealed a malnourished patient (both weight-for-age value and body-mass-index below the third percentile). Blood tests and negative IgA anti-endomysial antibodies excluded malabsorption as a cause of her malnutrition; endocrine work-up excluded thyroid dysfunction, growth hormone deficiency, and adrenal insufficiency. Magnetic resonance imaging (MRI) showed thickening of the pituitary stalk with a transverse diameter of 7 mm. The patient underwent a biopsy through a supraorbital eyebrow approach. Histopathological examination revealed lymphocytic hypophysitis, with tissue markers all negative for germinoma. The girl is currently under follow up with serial MRI every three months. CONCLUSION DS should be considered as a differential diagnosis in any child with failure to thrive, and imaging studies should be performed even if there are no additional neurological symptoms.
CBIO-03. ATRX LOSS IN GLIOMA RESULTS IN EPIGENETIC DYSREGULATION OF CELL CYCLE PHASE TRANSITION
Authors: Brendan Mullan, Tingting Qin, Ruby Siada, Ramya Ravindran, Chase Thomas, Micah Harris, Ashwat Muruganand, Kalyani Pyaram, Zachary Miklja, Mary Reiber, Taylor Garcia, Dustin Tran, Carla Danussi, Jackie Brosnan-Cashman, Drew Pratt, Xinyi Zhao, Alnawaz Rehemtulla, Maureen Sartor, Sriram Venneti, Alan Meeker, Jason Huse, Meredith Morgan, Pedro Lowenstein, Maria Castro, Viveka Nand Yadav, Carl Koschmann
Journal: Neuro-Oncology (2020)

Abstract Gliomas are a leading cause of cancer mortality in children and adults, and new targeted therapies are desperately needed. ATRX is a chromatin remodeling protein that is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and IDH-mutant grade 2/3 adult glioma. We previously showed that loss of ATRX in glioma results in tumor growth and additional tumor mutations. However, the mechanism driving these phenotypes has not been fully established. We found that in ChIP-Seq/ChIP-qPCR of mouse neuronal precursor cells (NPCs) and GBM cells with isogenic ATRX loss, ATRX binds regulatory elements for cell cycle phase transition gene sets, and ATRX loss subsequently results in reduced expression. Furthermore, human GBM cells with ATRX knock-out demonstrate higher rates of cells in S and G2/M phases, with clusters of cells demonstrating reduced expression of cell cycle regulatory gene sets by single-cell sequencing (scSeq) analysis. In human and mouse GBM in vitro models, ATRX-deficient cells exhibit a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation and enhanced activation of the master cell cycle regulator ATM with radiation. Treatment of ATRX-deficient gliomas with ATM inhibitors results in a selective increase in dysfunctional cell cycling and increased radio-sensitization in ATRX-deficient glioma cells. Using an ATM-luciferase reporter in orthotopically-implanted human GBM cells, both AZD0156 and AZD1390 demonstrate in vivo pathway inhibition. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate a doubling of median survival compared to radiated controls (p=0.0018) when treated with AZD0156 combined with radiation; this is not seen in ATRX-sufficient models. This study demonstrates that ATRX-deficient high-grade gliomas display epigenetic dysregulation of cell cycle phase transitions, which opens a new window for therapies targeting this unique phenotype.
Conductive Composite Fiber with Optimized Alignment Guides Neural Regeneration under Electrical Stimulation
Authors: Jin Zhang, Xi Zhang, Chenyu Wang, Feihan Li, Ziwen Qiao, Liangdan Zeng, Zhonghan Wang, He Liu, Jianxun Ding, Huanghao Yang
Journal: Advanced Healthcare Materials (2020)

Abstract Conductivity and alignment of scaffolds are two primary factors influencing the efficacy of nerve repair. Herein, conductive composite fibers composed of poly(ɛ‐caprolactone) (PCL) and carbon nanotubes (CNTs) with different orientation degrees are prepared by electrospinning at various rotational speeds (0, 500, 1000, and 2000 rpm), and meanwhile the synergistic promotion mechanism of aligned topography and electrical stimulation on neural regeneration is fully demonstrated. Under an optimized rotational speed of 1000 rpm, the electrospun PCL fiber exhibits orientated structure at macroscopic (mean deviation angle = 2.78°) or microscopic crystal scale (orientation degree = 0.73), decreased contact angle of 99.2° ± 4.9°, and sufficient tensile strength in both perpendicular and parallel directions to fiber axis (1.13 ± 0.15 and 5.06 ± 0.98 MPa). CNTs are introduced into the aligned fiber for further improving conductivity (15.69–178.63 S m −1 ), which is beneficial to the oriented growth of neural cells in vitro as well as the regeneration of injured sciatic nerves in vivo. On the basis of robust cell induction behavior, optimum sciatic nerve function index, and enhanced remyelination/axonal regeneration, such conductive PCL/CNTs composite fiber with optimized fiber alignment may serve as instructive candidates for promoting the scaffold‐ and cell‐based strategies for neural repair.