tbuckley/cabot-search huggingface dataset:
Multi-omics study of silicosis reveals the potential therapeutic targets PGD<sub>2</sub> and TXA<sub>2</sub>
Authors: Junling Pang, Xianmei Qi, Ya Luo, Xiaona Li, Ting Shu, Baicun Li, Meiyue Song, Ying Liu, Dong Wei, Jingyu Chen, Jing Wang, Chen Wang
Journal: Theranostics (2020)

Rationale: Silicosis is a severe occupational lung disease. Current treatments for silicosis have highly limited availability (i.e., lung transplantation) or, do not effectively prolong patient survival time (i.e., lung lavage). There is thus an urgent clinical need for effective drugs to retard the progression of silicosis. Methods: To systematically characterize the molecular changes associated with silicosis and to discover potential therapeutic targets, we conducted a transcriptomics analysis of human lung tissues acquired during transplantation, which was integrated with transcriptomics and metabolomics analyses of silicosis mouse lungs. The results from the multi-omics analyses were then verified by qPCR, western blot, and immunohistochemistry. The effect of Ramatroban on the progression of silicosis was evaluated in a silica-induced mouse model. Results: Wide metabolic alterations were found in lungs from both human patients and mice with silicosis. Targeted metabolite quantification and validation of expression of their synthases revealed that arachidonic acid (AA) pathway metabolites, prostaglandin D2 (PGD2) and thromboxane A2 (TXA2), were significantly up-regulated in silicosis lungs. We further examined the effect of Ramatroban, a clinical antagonist of both PGD2 and TXA2 receptors, on treating silicosis using a mouse model. The results showed that Ramatroban significantly alleviated silica-induced pulmonary inflammation, fibrosis, and cardiopulmonary dysfunction compared with the control group. Conclusion: Our results revealed the importance of AA metabolic reprogramming, especially PGD2 and TXA2 in the progression of silicosis. By blocking the receptors of these two prostanoids, Ramatroban may be a novel potential therapeutic drug to inhibit the progression of silicosis.
LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA
Authors: Stacy Chapman, Demitre Serletis, Colin Kazina, Mubeen Rafay, Sherry Krawitz, Katya Rozovsky, Magimairajan Issai Vanan
Journal: Neuro-Oncology (2020)

Abstract In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.
The Anti-B-Cell Maturation Antigen (BCMA) Antibody-α-Amanitin Conjugate Hdp-101 Induces Immunogenic Cell Death and Immunologic Memory in Models of Multiple Myeloma
Authors: Ram Kumar Singh, Richard J. Jones, Fazal M. Shirazi, Jianxuan M. Zou, Hua Wang, Hans C. Lee, Elisabet E. Manasanch, Isere Kuiatse, Andreas Pahl, Robert Z. Orlowski
Journal: Blood (2020)
Risk of Sudden Death in Asymptomatic Brugada Syndrome: Not as High as We Thought and Not as Low as We Wished…But the Contrary⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Sami Viskin, Raphael Rosso
Journal: Journal of the American College of Cardiology (2010)
EXTH-27. YAP/TAZ TRANSCRIPTIONAL CO-ACTIVATORS CREATE THERAPEUTIC VULNERABILITY TO VERTEPORFIN IN EGFR MUTANT GLIOBLASTOMA
Authors: Renee Read, Krishanthan Vigneswaran, Nathaniel Boyd, Se-Yeong Oh, Shoeb Lallani, Andrew Boucher, Stewart Neill, Jeffrey Olson
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM), neoplasms derived from glia and neuro-glial stem/progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months with current treatments. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases (RTKs), such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Using a Drosophila glioma model and human patient-derived GBM cells, we identified the YAP and TAZ transcription co-activators, effectors of the Hippo pathway that promote gene expression via TEAD co-factors, as key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling. YAP and TAZ are highly expressed in EGFR mutant human GBMs, and their knockdown in EGFR mutant GBM cells inhibits proliferation, blocks neuro-glial stem/progenitor cell fate, and elicits apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulate transcription of SOX2, C-MYC, and EGFR itself to create a feedforward loop to drive survival and proliferation as well as stem/progenitor cell fate in human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD mediated transcription, specifically induced apoptosis of cultured patient-derived GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe and verify verteporfin uptake into tumor cells in GBM tumors in human patients. Together, our data indicate that verteporfin is a promising therapeutic agent for EGFR amplified and mutant GBM. On the basis of these results, we have initiated as phase 1/2 clinical trial of Visudyne in patients with recurrent GBM characterized by EGFR amplification and/or mutation.
EPEN-25. EXCEPTIONAL CLINICAL AND IMAGING RESPONSE TO TRK-INHIBITION IN A PATIENT WITH SUPRATENTORIAL EPENDYMOMA HARBORING NTRK2 GENE FUSION
Authors: Ross Mangum, Jacquelyn Reuther, Adekunle Adesina, Marcia Kukreja, Daniel Curry, Fatema Malbari, Murali Chintagumpala, Donna M Muzny, Kevin Fisher, Angshumoy Roy, Kelsey C Bertrand, Stephen C Mack, Sharon E Plon, D Williams Parsons, Frank Y Lin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with metastatic pediatric ependymoma have limited therapeutic options and poor outcomes. Approximately ¾ of supratentorial ependymomas are driven by C11ORF95-RELA fusions, and the remaining by a heterogeneous group of fusion events. We present a six year-old male diagnosed with supratentorial ependymoma with leptomeningeal carcinomatosis harboring an NTRK2-fusion. Local and distant multifocal, intracranial and intraspinal tumor recurrence occurred seven months following gross total resection of the primary lesion and proton beam craniospinal irradiation. METHODS DNA and RNA from FFPE tumor were used for targeted sequencing using an 81-gene fusion panel and 124-gene mutation panel. Separately, capture transcriptome sequencing, exome sequencing, and copy number array were performed as part of the Texas KidsCanSeq study, an NHGRI/NCI-funded Clinical Sequencing Evidence-Generating Research (CSER) consortium project. All sequencing was carried out in CLIA-certified laboratories. RESULTS An in-frame fusion between 5’ exons 1–3 of KANK1 and 3’ exons 16–21 of NTRK2, predicted to retain the kinase domain, was identified. At tumor recurrence, therapy was initiated with Larotrectinib, an FDA-approved pan-TRK inhibitor. Clinical improvement in cognitive speed, motor strength, and coordination was observed at two weeks with significant tumor response on MRI at two and four months. CONCLUSION TRK gene fusions have not previously been reported in ependymoma. Further tumor characterization by methylation profiling is underway and will be of diagnostic interest given the apparent discordance between tumor histology and molecular findings. This case highlights the potential impact of clinical genomic analysis for children with CNS tumors.
NCOG-01. STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES AT THE GUY’S CANCER CENTER, LONDON: AN AUDIT FOR THE FIRST 17 MONTHS
Authors: Kallol Bhadra, Omar Al-Salihi, Sheila Hassan, Angela Swampillai, Kirsty Blythe, Samantha Forner, Caroline Sisodia, Lucy Brazil
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) commenced at Guy’s Cancer Hospital in August 2017. We report our first seventeen months’ data (August 2017 to December 2018) for brain metastases SRS. METHOD Patients referred via Neuro Oncology MDT were assessed for suitability for SRS via clinical review and 1mm-slice MRI. Treatment was planned on Eclipse v15.6 and delivered using Truebeam STx Linac(FFF) and Align RT v5.1 for matching. Dose prescription, according to departmental protocol, was set at 100% isodose, ranging from 18Gy to 25Gy, with fractionation varying from single to five fractions depending on factors including size, volume and locations. Post-treatment, patients were discharged back to their primary treating team for 3-monthly MRI. RESULTS Between Aug-17 to Dec-18, 70 patients with brain metastases were treated with a total of 122 lesions. Mean age was 66 years (range 37-93) and Median follow-up 9 months. Primary tumour sites mainly included lung 34(48.5%), breast 16(22.8%) and melanoma 17(24.3%). Brain-only metastases, including small volume primary with brain metastases were found in 85.4% cases, whilst visceral disease with brain metastases were found in 14.5% patients. Out of 122 lesions, the majority were treated in the primary setting; 95(77.8%) vs 27(22.1%) in the adjuvant setting. At 9-months follow up, local failure rate was in 26(21.3%) sites and 17 new sites in distant brain appeared. 31(44.2%) patients received no systemic therapy after SRS, whilst immunotherapy was received by 14(20%), with the remaining receiving hormones or chemotherapy. Median Overall Survival was 9.2 months (95% CI: 4.5-13.8) and Median progression-free survival was 5.9 months (95% CI: 7.0-10.4). CONCLUSION Overall Survival results were encouraging with initial auditing proving SRS as effective approach. Local control rates correlate well with randomized control trials results for SRS in brain metastases.
HGG-56. EXTENSIVE MOLECULAR HETEROGENEITY WITHIN H3-/IDH-WILDTYPE PEDIATRIC GLIOBLASTOMA
Authors: Mirjam Blattner-Johnson, Felix Sahm, Martin Sill, Dominik Sturm, Christof M Kramm, Stefan M Pfister, David Jones
Journal: Neuro-Oncology (2020)

Abstract About half of all pediatric high-grade gliomas (HGG) harbor mutations in histone 3 or IDH genes. The remaining HGG are currently broadly classified as H3-/IDH-wild-type. Since the introduction of a uniform approach to DNA methylation-based classification of CNS tumors in 2018, DNA methylation data from over 45,000 CNS tumor samples have been generated. From this large cohort, a number of smaller yet distinct subgroups start to emerge within H3-/IDH-wild-type HGG. Three such subgroups are enriched for focal gene amplifications and have been provisionally termed pedGBM_MYCN, pedGBM_RTK1 and pedGBM_RTK2. Since a significant subset of samples in each subgroup is lacking characteristic alterations, we further investigated the molecular and transcriptional composition of H3-/IDH-wild-type HGG. We evaluated DNA methylation and copy-number profiles in &amp;gt;1000 tumors classified as H3-/IDH-wild-type HGG. Tumors classified pedGBM_MYCN showed a focal MYCN amplification in 25%, with a similar fraction showing amplification of EGFR (8% of samples harbored both alterations) compared to 4% and 4% in pedGBM_RTK1 and 14% and 22% in pedGBM_RTK2. Deletion of CDKN2A/B was much more prevalent in the pedGBM_RTK2 subgroup (~50% compared to 27% in pedGBM_RTK1 and &amp;lt;10% in the pedGBM_MYCN group). We defined a pedGBM_MYCN transcriptional signature, which will be helpful in identifying subgroup-defining mechanisms and alterations. Initial results suggest an involvement of the sonic hedgehog pathway and genes controlling stem-cell pluripotency. Patient-derived xenograft models and murine neural stem cells are now being used for functional characterization and pre-clinical testing of potential drug targets in these molecularly defined subgroups.
Myocardial Edema Imaging of the Area at Risk in Acute Myocardial Infarction: Seeing Through Water⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Hassan Abdel-Aty
Journal: JACC. Cardiovascular imaging (2009)
ERK-dependent suicide gene therapy for selective targeting of RTK/RAS-driven cancers
Authors: Evan K. Day, Anne Campbell, Ashley Pandolf, Troy Rogerson, Qing Zhong, Aizhen Xiao, Benjamin Purow, Matthew J. Lazzara
Journal: Molecular Therapy (2020)

Suicide gene therapies provide a unique ability to target cancer cells selectively, often based on modification of viral tropism or transcriptional regulation of therapeutic gene expression. We designed a novel suicide gene therapy approach wherein the gene product (herpes simplex virus thymidine kinase or yeast cytosine deaminase) is phosphorylated and stabilized in expression by the extracellular signal-regulated kinase (ERK), which is overactive in numerous cancers with elevated expression or mutation of receptor tyrosine kinases or the GTPase RAS. In contrast to transcriptional strategies for selectivity, regulation of protein stability by ERK allows for high copy expression via constitutive viral promoters, while maintaining tumor selectivity in contexts of elevated ERK activity. Thus, our approach turns a signaling pathway often coopted by cancer cells for survival into a lethal disadvantage in the presence of a chimeric protein and prodrug, as highlighted by a series of in vitro and in vivo examples explored here.
EPID-14. GABRIELLA MILLER KIDS FIRST DATA RESOURCE CENTER: COLLABORATIVE PLATFORMS FOR ACCELERATING RESEARCH IN PEDIATRIC CANCERS &amp; STRUCTURAL BIRTH DEFECTS
Authors: Allison P Heath, Yuankun Zhu, Michele Mattioni, Bailey Farrow, Jena Lilly, Yiran Guo, Jo Lynne Rokita, Phillip B Storm, Samuel L Volchenboum, Javad Nazarian, Nicole Vasilevsky, Jack DiGiovanna, Melissa Haendel, Robert L Grossman, Brandi Davis-Dusenbery, Deanne M Taylor, Vincent Ferretti, Adam Resnick
Journal: Neuro-Oncology (2020)

Abstract Since launching to the public in September 2018, the Gabriella Miller Kids First Data Resource Center (DRC) has made an increasing number of pediatric genomic studies available to the research community. Currently, 1.3 PBs of genomic and clinical data drawn from 12,000 participants are available across a variety of pediatric cancer and structural birth defect studies. The DRC has architected a secure, cloud-based platform with over 1,300 users that supports the ability of researchers to not only find, access, and reuse data, but also integrate, collaborate, and analyze data quickly at scale. Users can use integrations with platforms such as Cavatica for bioinformatics workflows and PedcBioPortal for cancer genomic visualizations. Additionally, a set of framework services, powered by Gen3, provide a foundation for interoperability with other large-scale data sources, platforms, and a growing ecosystem of analysis and visualization applications. These integrations allow users to search across both TARGET and Kids First clinical data in one location while allowing data governance to be maintained by the original approvers. The new “explore data” feature allows users to search across all studies in order to identify virtual cohorts. Within the portal, these cohorts can be saved and shared with collaborators for iterative refinement and analysis. With appropriate approvals, the associated genomic data can be accessed and analyzed seamlessly in Cavatica or other platforms with interoperable framework services. Additionally, gene searching capabilities will be available in 2020. Data is free to download and cloud credits are available for analysis support.
DIPG-61. RESCUE REGIMENS AFTER BIOMEDE: POSSIBLE INFLUENCE ON OS ASSESSMENT
Authors: Daniela Di Carlo, Bertille Pommier, Gwenael Le Teuff, Samuel Abbou, Pablo Berlanga, Birgit Geoerger, Stephanie Puget, Kevin Beccaria, Thomas Blauwblomme, Marie-Anne Debily, David Castel, Emmanuelle Lechapt, Pascale Varlet, Volodia Dangouloff-Ros, Nathalie Boddaert, Gilles Vassal, Marie-Cécile Le Deley, Jacques Grill
Journal: Neuro-Oncology (2020)

Abstract BIOMEDE is a multicentric randomized phase II trial to evaluate in DIPG the OS of patients treated with dasatinib, erlotinib or everolimus. The OS is the result of the first line treatment but it could also be affected by re-irradiation and the second line treatment received after progression, especially in case of a possible crossover outside of the trial. This preliminary analysis focuses on the first patients enrolled at Gustave Roussy (n=37). The median age at diagnosis was 7 years, median interval from diagnosis to progression and median survival after progression were 7 (1–20) and 2 (0–13) months respectively. Initial treatment was everolimus for 13, dasatinib for 20, erlotinib for 4 patients. The most frequent targetable molecular alterations were mTOR pathway in 6, PDGRFA in 4, ACVR1 in 3 patients. Out of the 31 patients who relapsed and were evaluable, 18 and 13 had a median survival &amp;lt; 3 and &amp;gt; 3 months respectively. At relapse patients have received different types of therapies, in 6 cases matching the molecular profile of the tumour obtained by sequencing. At progression, seven patients switched from dasatinib to mTOR inhibitors and 2 patients switched from everolimus to dasatinib. Patients with OS after progression &amp;gt; 3 months had higher rate of reirradiation (77% vs 5%), steroid weaning (69% vs 33%) and Lansky/Karnowsky &amp;gt; 50% (85 vs 67%). Extended results on the entire cohort will be presented. It will be important to consider the distribution of reirradiation to interpret the results of the randomisation on OS.
Abstract 13117: Incorporation of High-Sensitivity Troponin Along With the AHA/ACC Cholesterol Guidelines for Improved Risk Stratification and Targeted PCSK9 Inhibition in Atherosclerotic Cardiovascular Disease
Authors: Nicholas A Marston, Kazuma Oyama, Minao Tang, Petr Jarolim, Peter S Sever, Anthony C Keech, Armando Lira Pineda, Huei Wang, Robert Giugliano, Marc S Sabatine, David A Morrow
Journal: Circulation (2020)

Introduction: The 2018 AHA/ACC cholesterol guidelines only recommend PCSK9 inhibitors in patients with very high risk ASCVD. However, high-sensitivity troponin (hsTn) can reclassify some lower risk patients as very high risk, identifying a subgroup who may benefit from PCSK9 inhibitors. Methods: We performed a nested prospective biomarker substudy including 22,224 patients enrolled in the FOURIER trial, which tested the PCSK9 inhibitor evolocumab. Per the guidelines, patients were assigned to ASCVD risk categories of “very high risk” or “not very high risk” (lower risk), followed by classification based on hsTnI (Abbott ARCHITECT) using an a priori risk threshold of 6 ng/L. The primary endpoint was a composite of CV death, MI, stroke, unstable angina, or coronary revascularization. The median follow-up was 2.2 years. Results: Clinical ASCVD categories alone identified a gradient of risk from 7.1% to 12.3% (HR 1.83, p&lt;0.0001). Adding hsTnI further risk stratified patients by 1.5- to 2-fold in both the lower and very high risk ASCVD categories (HR 1.73, p=0.017 &amp; HR 1.81, P&lt;0.0001). Among patients with lower risk ASCVD, 25% had an elevated hsTnI and carried a similar risk (10.5%) to patients with very high risk ASCVD and low hsTnI (9.8%). Very high risk ASCVD patients receiving evolocumab had an absolute risk reduction of 1.9% (0.98-2.72). A similar absolute risk reduction was seen in the 25% of patients in the lower risk group with elevated hsTnI (ARR 2.0%, Figure). Conclusions: Either hsTn or ASCVD clinical criteria can identify patients who benefit from evolocumab. Specifically, hsTnI identifies a significant cohort of nominally lower risk ASCVD patients who are actually at greater risk than appreciated and may derive absolute risk reductions on par with very high risk ASCVD patients.
It takes one meeting to increase awareness of eosinophilic esophagitis
Authors: Tim Vanuytsel
Journal: Endoscopy (2020)

Eosinophilic esophagitis (EoE) is a chronic food allergen-driven condition of the esophagus, resulting in tissue remodeling with fibrosis and ultimately strictures in a considerable proportion of patients if left untreated [1]. Since its first description in the early nineties, the management of EoE has changed significantly, from short, intermittent courses of corticosteroids to chronic maintenance therapy, similarly to the treatment paradigms in other chronic inflammatory conditions such as allergic asthma or inflammatory bowel disease. Current guidelines recommend chronic treatment with a proton-pump inhibitor, low-dose swallowed topical corticosteroids, or elimination diets [2]. Patients under maintenance therapy were more likely to achieve clinical, endoscopic, and histologic remission and had a reduced need for endoscopic dilations for esophageal strictures [3]. However, a correct and timely diagnosis is the critical first step in the management of EoE.