tbuckley/cabot-search huggingface dataset:
ATRT-02. MEK/ERK SIGNALLING DEPENDENCY IN ATYPICAL TERATOID RHABDOID TUMOURS
Authors: Hui (Claire) Shi, Dhanya Sooraj, Claire Sun, Paul Daniel, Gabrielle Bradshaw, Jason Cain, Ron Firestein
Journal: Neuro-Oncology (2020)

Abstract Atypical teratoid rhabdoid tumours (ATRTs) are high-grade malignant paediatric brain tumours with a less than one-year survival rate after diagnosis. Current treatment for ATRT, which includes high-intensive radiotherapy and chemotherapy, results in long-term side effects on ATRT patients. Hence, there is an urgent need to discover targeted therapies that could be used to treat patients with ATRT. As part of the Hudson Monash Paediatric Precision Medicine Program, we have collected 23 ATRT cell lines which we used to performed high-throughput small molecule and genetic (CRISPR) screening to identify new therapies and therapeutic targets. In parallel, we characterised the ATRT cell lines based on transcriptomic (RNA-seq) and epigenetic (methylation) signatures. An integrative multi-omic approach was then used to uncover discrete vulnerabilities in specific subsets of ATRT patients. Strikingly, these include a number of druggable dependencies, such as MEK, CDK, HDAC, and Topoisomerase, that offer a promise of rapid clinical translation. In our study, we focus on MEK dependency in a subtype of ATRT lines to further define the underlying mechanisms and biomarkers. While future studies validating the MEK/ERK signalling dependency in a wider cohort of patient models and in in vivo models are required, these data provide a framework for applying an integrative multi-omic approach in paediatric cancer precision medicine.
QOL-34. CAREER FAIR AND RESOURCE EXPO: ADVOCATING FOR THE LONG TERM SUCCESS OF BRAIN TUMOR SURVIVORS
Authors: Clay Hoerig, Karlie Allen, Kara Noskoff, Jamie Frediani, Jody Pathare, Casey Koerner, Veronica DeRosa, Nina Madrid, Kristin Miller, Grace Mucci, Chenue Abongwa, Ashley Plant
Journal: Neuro-Oncology (2020)

Abstract Pediatric cancer survivors have increased unemployment and lower educational attainment rates. This is most significant in brain tumor survivors who show five-fold relative odds increase in unemployment over other pediatric cancer survivors. The long-term effects of brain tumor treatment potentiate the difficulty with work and school reintegration seen in the broader Adolescent and Young Adult (AYA) population. To address this, our team designed an annual job fair for AYA Neuro-Oncology survivors. Vendors were invited representing disability advocacy groups, legal services, scholarship organizations, and employers with strong disability services, several who offered on-site interviews. Additionally, brain tumor survivors served as inspirational speakers for the event. Between thirty to forty survivors have attended each event. Pre- and post-surveys, as well as 3- and 6- month follow up was obtained. Universally, the day was engaging and motivating, both for survivors and staff, and stimulated conversation for pursuing career or academic success within families and the care team. While all the patients took applications, none of the patients completed the on-site interviews, finding them overwhelming. Even at the 3- and 6-month follow-ups following the first event, the survivors continued to be at varying levels of application completion; no one who was previously unemployed attained new employment. This improved after pre-event meetings were held with survivors to participate in resume building and interview preparation. Currently, two survivors obtained employment and are still employed at 1 year and five survivors were able to advocate for their disabilities services in college with help of a non-profit legal assistant.
Mutation clearance and complete radiologic resolution of immunotherapy relapsed metastatic melanoma after treatment with nivolumab and olaparib in a patient with homologous recombinant deficiency: any role for PARP inhibitors and checkpoint blockade?
Authors: K. Khaddour, M. Ansstas, J. Visconti, G. Ansstas
Journal: Annals of Oncology (2020)
JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis
Authors: Anna Sophie Klaeschen, Tim Joachim Nümm, Nadine Herrmann, Nicole Leib, Laura Maintz, Takashi Sakai, Joerg Wenzel, Thomas Bieber
Journal: Journal of Allergy and Clinical Immunology (2020)
MBRS-01. DISSECTING REGULATORS OF THE ABERRANT POST-TRANSCRIPTIONAL LANDSCAPE IN MYC-AMPLIFIED GROUP 3 MEDULLOBLASTOMA
Authors: Michelle Kameda-Smith, Helen Zhu, EnChing Luo, Chitra Venugopal, Agata Xella, Kevin Brown, Raymond Fox, Brian Yee, Sansi Xing, Frederick Tan, David Bakhshinyan, Ashley Adile, Minomi Subapanditha, Daniel Picard, Jason Moffat, Adam Fleming, Kristin Hope, Provias John, Marc Remke, Yu Lu, Tannishitha Reya, Juri Reimand, Robert Wechsler-Reya, Gene Yeo, Sheila Singh
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that an RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. Unbiased integrative multi-omics analysis of MSI1 function in human G3 MB suggests a paradigm shift beyond traditional gene-based profiling of oncogenes. Here we identify MSI1 as an oncogene in G3 MB driving stem cell self-renewal through stabilization of HIPK1 mRNA, a downstream context-specific therapeutic target for drug discovery.
DDEL-17. TRIPLE INTRAVENTRICULAR CHEMOTHERAPY FOR TREATMENT OF RELAPSED CHOROID PLEXUS CARCINOMA
Authors: Grace Lau, Lisa Janson, Julie Drummond, Nataliya Zhukova, Paul Wood
Journal: Neuro-Oncology (2020)

Abstract Limited evidence for the optimal management of relapsed choroid plexus carcinoma (CPC) exists, with a few case reports involving surgery, radiotherapy and intravenous chemotherapy. However, the safety and tolerability of intraventricular chemotherapy in this setting has not been widely studied. We describe a case where triple intraventricular chemotherapy was administered to a child with relapsed metastatic CPC. A 7-year-old male with a history of CPC presented with relapsed metastatic disease. At initial diagnosis at 4 years of age, treatment involved gross total resection of an intraventricular mass in the left temporal region followed by chemotherapy and autologous stem cell transplantation (SCT) according to HEADSTART II-D. One year after SCT, craniospinal radiation was delivered following radiological relapse, achieving a partial response. Given previous treatment-limiting myelosuppression, intraventricular chemotherapy via Ommaya® reservoir with thiotepa 5mg, etoposide 0.5mg and topotecan 0.4mg twice a week (non-weight-based dosing) was commenced taking into consideration pharmaceutical formulation aspects for optimal intraventricular drug delivery. After six cycles of intraventricular chemotherapy, palliative radiotherapy was administered due to radiological progression. Following completion, weekly triple intraventricular chemotherapy continued for 9 months. The patient remained out of hospital with the main side effects being fatigue and occasional nausea amenable to ondansetron. This case study demonstrates the safety and tolerability of a triple intraventricular chemotherapy regimen used to delay disease progression and prolong quality of life in a child with relapsed CPC in the palliative setting. This could provide an alternative treatment regimen for patients with relapsed disease.
Abstract 10298: Clinical Usefulness of New R-R Interval Analysis Using Heart Rate Sensor WHS-1 to Identify Sleep Apnea Syndrome (SAS)
Authors: Takuo Arikawa, Toshiaki Nakajima, Akiko Haruyama, Hiroyuki Kaneda, Shigeru Toyoda, Masao Nishimura, Tsutsumi Takeshi, Taishi Matsui, Akio Nakata, Teruo Inoue
Journal: Circulation (2019)

Introduction: Sleep apnea syndrome (SAS) is highly associated with cardiovascular diseases, and life prognosis. The number of patients with SAS is about 1.5 million nationwide, and the number of po...
Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits
Authors: Shreyas Bhat, Ali El-Kasaby, Michael Freissmuth, Sonja Sucic
Journal: Pharmacology & Therapeutics (2020)

Neurotransmitters, such as γ-aminobutyric acid, glutamate, acetyl choline, glycine and the monoamines, facilitate the crosstalk within the central nervous system. The designated neurotransmitter transporters (NTTs) both release and take up neurotransmitters to and from the synaptic cleft. NTT dysfunction can lead to severe pathophysiological consequences, e.g. epilepsy, intellectual disability, or Parkinson's disease. Genetic point mutations in NTTs have recently been associated with the onset of various neurological disorders. Some of these mutations trigger folding defects in the NTT proteins. Correct folding is a prerequisite for the export of NTTs from the endoplasmic reticulum (ER) and the subsequent trafficking to their pertinent site of action, typically at the plasma membrane. Recent studies have uncovered some of the key features in the molecular machinery responsible for transporter protein folding, e.g., the role of heat shock proteins in fine-tuning the ER quality control mechanisms in cells. The therapeutic significance of understanding these events is apparent from the rising number of reports, which directly link different pathological conditions to NTT misfolding. For instance, folding-deficient variants of the human transporters for dopamine or GABA lead to infantile parkinsonism/dystonia and epilepsy, respectively. From a therapeutic point of view, some folding-deficient NTTs are amenable to functional rescue by small molecules, known as chemical and pharmacological chaperones.
Abstract 13188: Prognostic Assessment of the IABP-SHOCK II Risk Score in a Contemporary North American Population From the Critical Care Cardiology Trials Network Registry
Authors: Carlos L Alviar, Erin A Bohula, Vivian M Baird-Zars, Jason N Katz, Sean Van Diepen, David A Morrow
Journal: Circulation (2019)

Background: Risk stratification has potential to guide triage and therapeutic decision-making in pts with cardiogenic shock (CS). Our aim was to assess the prognostic performance of the IABP-SHOCK ...
EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES
Authors: Nikita Dhir, Sheila Chandrahas, Chibuzo O’Suoji, Mohamad Al-Rahawan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation. OBJECTIVE Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors. METHODS We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy. DISCUSSION Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors. CONCLUSION The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.
Modifiable Factors Associated With Chronic Pain 1 Year After Operative Management of Distal Radius Fractures
Authors: Alfred P. Yoon, Chang Wang, Kelly A. Speth, Lu Wang, Kevin C. Chung
Journal: JAMA Network Open (2020)

Despite appropriate treatment, many patients who sustain distal radius fractures (DRFs) report persistent wrist pain. Chronic musculoskeletal pain is among the leading health problems in the elderly population associated with significant personal and societal burden.To identify modifiable preoperative factors that are significantly associated with developing chronic pain.This is a secondary analysis of the Wrist and Radius Injury Surgical Trial (WRIST), a randomized multicenter clinical trial of 24 study sites in the United States, Canada, and Singapore that enrolled patients from April 10, 2012, to December 31, 2016. Adults older than 60 years who sustained closed extra-articular DRFs, were treated operatively, and completed 12-month Michigan Hand Outcomes Questionnaires (MHQs) were included in this study. Analysis was conducted from September to December 2019.Volar locking plate internal fixation, external fixation, or percutaneous pinning.12-month MHQ pain domain score. Inverse probability weighted logistic regression was used to identify factors associated with of chronic pain.A total of 146 patients with DRF who were treated operatively and had 12-month MHQ scores met inclusion criteria. The mean (SD) patient age was 68.9 (7.2) years, 128 (87.6%) were women, and 93 (63.7%) were retired. Chronic pain was present in 87 patients (59.6%) and absent in 59 patients (40.4%) at 1-year follow-up. A 1-week delay in surgery was associated with more than triple the odds of developing chronic pain (odds ratio [OR], 3.65; 95% CI, 1.48-9.00), and each 10-point increase in preoperative pain was associated with a 17% increase in the odds of experiencing chronic pain (OR, 1.17; 95% CI, 1.02-1.34). Internal fixation was associated with decreased odds of developing chronic pain compared with the other 2 procedures (OR, 0.29; 95% CI, 0.10-0.90).In this study, preoperative pain, time to surgery, and procedure type were modifiable factors associated with chronic pain 1 year after DRF treated with surgery. Adequate pain control in patients with acute DRFs even before definitive surgical management and earlier fixation for patients requiring surgery may decrease the risk of developing chronic pain. Internal fixation may decrease the risk of chronic pain after DRF surgery, compared with percutaneous pinning or external fixation.ClinicalTrials.gov Identifier: NCT01589692.
IMMU-18. INTERPLAY BETWEEN IDH1 AND ATRX MUTATIONS GOVERN INNATE IMMUNE RESPONSES IN GLIOMAS
Authors: Seethalakshmi Hariharan, Michelle Bowie, Janell Hostettler, Kristen Roso, Yiping He, Martin A Roskoski, Casey Charbonneau, Stephen Keir, Michael Brown, David Irvin, Gao Zhang, Matthias Gromeier, Jason Huse, David Ashley
Journal: Neuro-Oncology (2020)

Abstract Innate-based immunotherapies are becoming increasingly important for treating brain tumor patients. About 50% of WHO grade II and III gliomas carry mutations in IDH1 and ATRX genes. Mutant IDH1 results in the production of 2-hydroxyglutarate, an oncometabolite that promotes global metabolic and epigenetic alterations. ATRX is a SWI-SNF chromatin remodeling protein that is involved in cell cycle regulation and maintenance of genomic stability. Both IDH1 and ATRX mutations have been implicated in dysfunctional immune signaling in cancer cells. However, the interplay between these mutations in mediating innate immune responses has not been investigated in gliomas. We have derived human and mouse glioma cell lines carrying mutations in IDH1 (IDH1R132H) and/or ATRX, which we then used to generate both immune competent and nude mice models. Treating the ATRX knockout (KO) cell lines with dsRNA-based innate stimuli led to an early induction in phospho-IRF3, and late induction in phospho-STAT1 and ISG15, suggesting that ATRX deletion may enable a potent activation of type I interferon production and sensitize glioma cells to dsRNA-based innate stimuli. Our syngeneic murine glioma models confirm a survival advantage for mice carrying ATRX-KO tumors. These tumors also exhibit enhanced infiltration of T-cells and expression of activated macrophage markers. On the other hand, presence of IDH1R132H led to a suppression in baseline expression of key innate immune players, which could be rescued by the mutant IDH1 inhibitor, BAY-1436032. Cells harboring IDH1R132H and ATRX-KO retained sensitivity to dsRNA indicating that IDH1R132H does not dampen the ATRX KO-mediated sensitivity to dsRNA. Our models are under evaluation with a combination of BAY-1436032 and clinically relevant dsRNA-based innate therapies. Our data indicates the presence of an interplay between IDH1 and ATRX mutations that may regulate innate signaling in gliomas. Understanding the mechanisms governing this interplay may aid in designing therapies that exploit this interplay.
Abstract P377: Changes in Leisure-time Physical Activity and Risk of Ischemic and Hemorrhagic Stroke: The Atherosclerosis Risk in Communities Study
Authors: Logan Cowan, Yelena Tarasenko, Priya Palta, Kelly R Evenson, Kamakshi Lakshminarayan
Journal: Circulation (2020)

Introduction: Engagement in leisure-time physical activity (PA) levels recommended by the American Heart Association (AHA) is inversely associated with both ischemic and hemorrhagic stroke risk. PA levels fluctuate over the lifecourse, but the association between changes in PA from mid- to late-life and stroke risk is unknown. Hypothesis: Participants who maintained ideal levels of PA or increased their PA across 6 years will have lower ischemic and hemorrhagic stroke risk relative to those who had persistently poor PA. Methods: We included 11,658 participants of the Atherosclerosis Risk in Communities study without a history of CHD or stroke at visit 3 (1993-1995). Leisure-time PA was assessed using the modified Baecke questionnaire at visits 1 and 3 and categorized according to the AHA guidelines for PA (ideal, intermediate, or poor). All adjudicated definite and probable incident ischemic and hemorrhagic strokes between visit 3 and end of year 2013 were included. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ischemic and hemorrhagic stroke by categories of PA at visits 1 and 3. Those with poor PA at both visits were the referent group. We adjusted for age, sex, race/center, smoking, alcohol consumption, hypertension, diabetes mellitus, LDL, HDL, triglycerides, and body mass index. Results: During a median of 18.7 years of follow-up, 640 incident ischemic strokes and 76 hemorrhagic strokes occurred. In adjusted analyses, participants with ideal PA at both visits had a significantly lower ischemic stroke risk (HR=0.75 (0.59, 0.96)) but not significantly lower hemorrhagic stroke risk (HR=1.27 (0.65, 2.48)). Those whose PA levels increased from poor to ideal also had lower ischemic stroke risk (HR=0.74 (0.54, 1.03)) but not hemorrhagic stroke risk (HR=0.74 (0.28, 2.02)). Conclusion: Increasing PA between visit 1 and visit 3 was associated with lower ischemic stroke risk. Increasing PA may be an important component of stroke prevention.
IMMU-21. INVESTIGATION OF WHITE BLOOD CELL CHARACTERISTICS IN CSF SAMPLES AT PEDIATRIC BRAIN TUMOR DIAGNOSIS
Authors: Hunter Greer, Kristen Campbell, Sadaf Samay, Adam Green
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND There has been a recent surge in investigation of immunity and immunotherapy, but their role in pediatric brain tumors is incompletely defined. We hypothesized that investigating an understudied dataset, WBC and differential results in CSF drawn at the time of pediatric brain tumor diagnosis to look for microscopic metastases, would provide insight into the role of immunology and potential for immunotherapy in these diseases and correlate with prognosis and/or metastasis. METHODS We conducted a retrospective comparison analysis of CSF values in 349 patients at our institution from samples drawn within 60 days of initial CNS tumor diagnosis from 1998–2018. We examined total nucleated cell count, absolute counts and percentages for WBC subtypes. We compared CSF values by tumor cell presence, patient vital status, and disease group: atypical teratoid rhabdoid tumor, ependymoma, germinoma, high-grade glioma (HGG), low-grade glioma (LGG), medulloblastoma, non-germinomatous germ cell tumor, and other embryonal tumors (OET). We used Wilcoxon and Kruskal-Wallis tests for comparisons. RESULTS Overall, higher lymphocyte percentage (p=0.002) and lower monocyte percentage (p=0.007) were associated with survival. WBC characteristics did not differ significantly based on tumor cell presence. Compared to medulloblastoma, ependymoma showed a more active CSF immune response, while LGG, HGG, and OET showed a less active response, based on total WBC and/or absolute neutrophil count (p=0.001–0.007). CONCLUSIONS Higher lymphocyte and lower monocyte percentages in CSF correlated with better prognosis overall; causality requires further investigation. Tumor subtypes varied in their immune stimulation, offering potential insight into which will be amenable to immunotherapy.
SeSaMe PS Function: Functional Analysis of the Whole Metagenome Sequencing Data of the Arbuscular Mycorrhizal Fungi
Authors: Jee Eun Kang, Antonio Ciampi, Mohamed Hijri
Journal: Genomics Proteomics & Bioinformatics (2020)

In this study, we introduce a novel bioinformatics program, Spore-associated Symbiotic Microbes Position-specific Function (SeSaMe PS Function), for position-specific functional analysis of short sequences derived from metagenome sequencing data of the arbuscular mycorrhizal fungi. The unique advantage of the program lies in databases created based on genus-specific sequence properties derived from protein secondary structure, namely amino acid usages, codon usages, and codon contexts of 3-codon DNA 9-mers. SeSaMe PS Function searches a query sequence against reference sequence database, identifies 3-codon DNA 9-mers with structural roles, and creates a comparative dataset containing the codon usage biases of the 3-codon DNA 9-mers from 54 bacterial and fungal genera. The program applies correlation principal component analysis in conjunction with K-means clustering method to the comparative dataset. 3-codon DNA 9-mers clustered as a sole member or with only a few members are often structurally and functionally distinctive sites that provide useful insights into important molecular interactions. The program provides a versatile means for studying functions of short sequences from metagenome sequencing and has a wide spectrum of applications. SeSaMe PS Function is freely accessible at www.fungalsesame.org.