tbuckley/cabot-search huggingface dataset:
PATH-27. MUTATION DETECTION USING PLASMA CELL-FREE DNA IN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Ross Mangum, Jacquelyn Reuther, Koel Sen Baksi, Ryan C Zabriskie, Ilavarasi Gandhi, Alva Recinos, Samara L Potter, Frank Y Lin, Murali Chintagumpala, Donna M Muzny, Kevin Fisher, Sharon E Plon, Angshumoy Roy, D Williams Parsons
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The role of plasma cell-free DNA (cfDNA) as a cancer biomarker for tracking treatment response and detecting early relapse has been well described for solid tumors outside the central nervous system (CNS). However, the presence of a blood-brain barrier complicates the application of plasma cfDNA analysis for patients with CNS malignancies. METHODS cfDNA was extracted from plasma of pediatric patients with CNS tumors utilizing a QIAmp® MinElute® kit and quantitated with Qubit 2.0 Fluorometer. Extensive genomic testing, including targeted DNA and RNA solid tumor panels, exome and transcriptome sequencing, as well as copy number array, was performed on matched tumor samples as part of the Texas KidsCanSeq study. An Archer® Reveal ctDNA28 NGS kit was then used for assaying the sensitivity of detecting tumor-specific mutations in the plasma of these patients. RESULTS A median of 10.7ng cfDNA/mL plasma (Interquartile range: 6.4 – 15.3) was extracted from 78 patients at time of study enrollment. Longitudinal samples from 24 patients exhibited a median yield of 7.7ng cfDNA/mL plasma (IQR: 5.9 – 9.1). An initial cohort of 6 patients was identified with 7 somatic variants covered by the Archer® Reveal kit. Four of seven mutations identified in matched tumor specimens were detected in patient plasma at variant allele frequencies ranging from 0.2–1%. CONCLUSIONS While challenging, detection of cfDNA in the plasma of pediatric patients with CNS tumors is possible and is being explored in a larger patient cohort along with pilot studies investigating cerebrospinal fluid as an additional source for tumor-specific cfDNA.
LINC-36. TRILATERAL RETINOBLASTOMA: A REPORT OF FOUR CASES
Authors: Ludi Dhyani Rahmartani
Journal: Neuro-Oncology (2020)

Abstract Retinoblastoma is the most common primary malignant intraocular cancer that usually develops in early childhood. About 5% of those patients are at risk of developing trilateral retinoblastoma (TRB). In developing countries, most of them came in the late stage; therefore, ocular and patient survival rates are lower than in developed countries. From 2015–2019, we found four cases of trilateral retinoblastoma. Two of them had bilateral retinoblastoma, and two had unilateral retinoblastoma. They all presented with leukocoria and had no family history of retinoblastoma. The mean age was 13.8 months (range 9–24 months of age). The diagnosis of trilateral retinoblastoma was made from initial head CT/MRI. They were treated conservatively with high dose VEC chemotherapy, and three of them have died during treatment. Trilateral retinoblastoma is usually fatal and needs multidisciplinary treatment care. In developing countries, it is important to evaluate distant metastasis. Head CT or MRI from the initial diagnosis to exclude the trilateral retinoblastoma.
Maximizing the Uptake of a COVID-19 Vaccine in People With Severe Mental Illness
Authors: Nicola Warren, Steve Kisely, Dan Siskind
Journal: JAMA Psychiatry (2020)

People with serious mental illness (SMI) are at increased risk of being infected by coronavirus disease 2019 (COVID-19) and have higher subsequent rates of hospitalization, morbidity, and mortality. 1,2Factors that contribute to worse outcomes include concomitant medications, poorer premorbid general health, physical comorbidity, reduced access to medical care, and environmental and lifestyle factors such as lower socioeconomic status, overcrowding, smoking, or obesity.In light of these vulnerabilities, it is important that people with SMI are a priority group to receive a vaccination, should one be developed and deemed safe and effective. 3De Hert and colleagues 3 noted that there is an ethical duty to prioritize vaccination for people with SMI given their increased risk of worse outcomes following COVID-19 infection and the structural barriers faced by people with SMI in accessing a vaccine.In addressing the Framework for Equitable Allocation of the COVID-19 Vaccine 4 principle mitigation of health inequities, people with SMI should be included with other priority groups, including Indigenous people, older adults, and people with physical health comorbidities.Over and above the ethical need to ensure vaccination allocation priority for people with SMI, evidence from existing vaccination programs suggests that there are challenges in achieving this aim at both an individual and public health level.People with SMI are less likely to receive preventive or guideline-appropriate health care for concerns such as cardiovascular disease and cancer.This reduced access to preventive care is reflected in the low uptake of immunizations recommended for adults among people with SMI.Of these, influenza may serve as a particularly useful model given the recommendation for an annual vaccination.In contrast with other vulnerable groups in the United States, influenza vaccination rates among people with SMI are as low as 25%. 5,6Based on the experience with influenza vaccination programs, we have outlined key barriers and solutions to access any potential COVID-19 vaccine for people with SMI (Table ).
PATH-22. COMPARISON OF SUPERVISED CLASSIFICATION METHODS FOR CENTRAL NERVOUS SYSTEM TUMORS BASED ON DNA-METHYLATION
Authors: Brent Orr, Alex Breuer, Tong Lin, Quynh Tran, Edward Suh, Stanley Pounds
Journal: Neuro-Oncology (2020)

Abstract Classification of brain tumors using methylation profiling is an important diagnostic advance, reducing subjectivity and improving interpretability of clinical outcome data. Despite the recognized value of methylation profiling in the clinical laboratory, the performance characteristics of different supervised classification models has not been directly compared. We developed 3 methods using methylation profiles to classify CNS tumors: an exact bootstrap k-nearest neighbor (kNN), a multi-layer perceptron neural net (NN), and a random forest classifier (RF). We trained these methods on the publicly available CNS tumor reference cohort (GSE90496) with 2,801 profiles and 91 classes. We evaluated the performance of these methods by leave-out-25% cross-validation. The relative performance of these methods were evaluated in terms of accuracy, precision, and recall for class or class family. The kNN, RF, and NN classifier had an estimate error rate of 10.74%, 4.01%, and 1.89%, respectively for class prediction and an error rate for family prediction of 5.97%, 0.90%, and 0.6%, respectively. At perfect recall for class assignment, the RF and kNN had a precision of 0.96 and 0.89 while the NN reached 0.98. For family assignment, the precision for the three classifiers was almost 1.0 with recall of nearly 0.8. At the recall rate of 1.0, the precision dropped to 0.94, 0.991 and 0.994 for kNN, RF, and NN, respectively. Overall, the NN showed improved performance metrics compared to the kNN and RF in CNS tumor classification for both class and class family assignment.
Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in <i>BRCA2</i>-altered Prostate Tumors
Authors: Goutam Chakraborty, Nabeela Khan Patail, Rahim Hirani, Subhiksha Nandakumar, Ying Z. Mazzu, Yuki Yoshikawa, Mohammad Atiq, Lina E. Jehane, Konrad H. Stopsack, Gwo-Shu Mary Lee, Wassim Abida, Michael J. Morris, Lorelei A. Mucci, Daniel Danila, Philip W. Kantoff
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Alterations in DNA damage repair (DDR) pathway genes occur in 20%–25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable. Experimental Design: We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2 null with BRCA2 wild-type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids. Results: We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in BRCA2-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in BRCA2-null prostate cancer cells. Moreover, SRC knockdown increased PARPi sensitivity in BRCA2-null prostate cancer cells. Conclusions: This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.
EXTH-19. EVALUATING THE ANTI-TUMOR EFFECT OF A NOVEL THERAPEUTIC AGENT, MAGMAS INHIBITOR, IN MALIGNANT GLIOMA
Authors: Kaijun Di, Senjie Du, Javier Lepe, Nitesh Nandwana, Bhaskar Das, Daniela Bota
Journal: Neuro-Oncology (2020)

Abstract BACKGROUNDS Glioblastoma (GBM) is an aggressive infiltrative brain tumor, and has an extremely poor prognosis despite the use of multiple treatment modalities, including surgery, radiation, and chemotherapy. Meanwhile, mitochondrial changes represent a significant part of cancer cell biology since cancer cells must survive and adapt to challenging microenvironments, specifically in conditions where tumor growth makes oxygen and glucose scarce. As GBM is characterized by extensive hypoxia-induced phenotypic changes such as abnormal vascular proliferation and necrosis, regulation of mitochondrial function could be a novel approach for treating GBM that currently lacks effective therapies. Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes for the mitochondrial import inner membrane translocase subunit Tim16. We previously demonstrated that a novel Magmas inhibitor, BT#9, significantly exerted anti-tumor effect in glioma in vitro, and may cross the blood brain barrier in vivo, indicating that Magmas inhibitor may be a new chemotherapeutic agent for the treatment of GBM. METHODS In this study, the antitumor effect of Magmas inhibitor BT#9 was tested in an orthotopic xenograft model of human GBM. The molecular mechanism of BT#9 was investigated using glioma cell lines. RESULTS The mice were tolerated to BT#9, and there was no statistical difference in the weight of animals between the control and MTD (Maximum-tolerated Dose, 50mg/kg) groups. The immunocompromised mice, intracranially implanted with human D-54 GBM xenografts, survived significantly longer than the controls (P&amp;lt; 0.5) when treated with BT#9 at MTD. In vitro study showed that the MAP kinase pathways are involved in BT#9-induced tumor suppression. DISCUSSION This is the first study on the role of Magmas in glioma in vivo. Our findings suggested that Magmas plays a key role in glioma survival and targeting Magmas by Magmas inhibitor has the potential to become a therapeutic strategy in glioma patients.
PATH-08. EVALUATION OF MISMATCH REPAIR GENE EXPRESSION BY IMMUNOHISTOCHEMISTRY MAY DETECT EARLY PHASE OF MMR DEFICIENCY IN RECURRENT GLIOMAS
Authors: Fumi Higuchi, Hadzki Matsuda, Takeo Uzuka, Phyo Kim, Keisuke Ueki
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Mismatch Repair (MMR) Deficiency is common in recurrent gliomas from IDH-mutant and IDH-wild-type tumors. Emergence of MMR deficit is strongly associated with the chemotherapy using TMZ, and it is considered to be a key mechanism of acquiring resistance to TMZ. Several studies showed MMR protein loss detected by immunohistochemistry was well concordant with molecular genetics sequencing data, and sometimes even more reliable in detecting MMR functional deficit. Here we evaluated Mismatch Repair protein expression by immunohistrochemistry for the pairs of primary and recurrent gliomas. METHODS We investigated the expression of 4 MMR proteins (MLH1/MSH2/MSH6/PMS2) in 37 cases of paired primary-recurrent gliomas (7 grade II &amp; III astrocytomas, 16 grade II &amp; III oligodendrogliomas, and 14 glioblastomas). Clinical information including history of chemo-radiotherapy after primary surgery were collected retrospectively. RESULTS Except for one case of GBM, all primary tumors retained 4 MMR proteins. 10 of 37 recurrent tumors lost one or more MMR protein expression (4 GBM 3 astrocytoma, 3 oligodendroglioma), including one case in which primary tumor already had MSH2/MSH6 loss. 2 recurrent GBM lost MMR protein expression homogenously, while in other 8 tumors, the patterns of MMR protein loss were heterogenous. 8 of 10 tumors that lost MMR protein expression were recurrence after TMZ treatment. CONCLUSION Although the interpretation of the heterogenous loss of MMR protein expression is somewhat difficult, the immunohistochemical evaluation of MMR proteins appears to be feasible, and may be able to detect early phase of MMR deficiency and the rise of hypermutator phenotype.
Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission
Authors: Hui-Fang Hu, Wen Wen Xu, Yang-Jia Li, Yan He, Wei-Xia Zhang, Long Liao, Qi-Hua Zhang, Lei Han, Xing-Feng Yin, Xiao-Xu Zhao, Yun-Long Pan, Bin Li, Qing-Yu He
Journal: Theranostics (2020)

This study aimed to screen novel anticancer strategies from FDA-approved non-cancer drugs and identify potential biomarkers and therapeutic targets for colorectal cancer (CRC). Methods: A library consisting of 1056 FDA-approved drugs was screened for anticancer agents. WST-1, colony-formation, flow cytometry, and tumor xenograft assays were used to determine the anticancer effect of azelastine. Quantitative proteomics, confocal imaging, Western blotting and JC-1 assays were performed to examine the effects on mitochondrial pathways. The target protein of azelastine was analyzed and confirmed by DARTS, WST-1, Biacore and tumor xenograft assays. Immunohistochemistry, gain- and loss-of-function experiments, WST-1, colony-formation, immunoprecipitation, and tumor xenograft assays were used to examine the functional and clinical significance of ARF1 in colon tumorigenesis. Results: Azelastine, a current anti-allergic drug, was found to exert a significant inhibitory effect on CRC cell proliferation in vitro and in vivo, but not on ARF1-deficient or ARF1-T48S mutant cells. ARF1 was identified as a direct target of azelastine. High ARF1 expression was associated with advanced stages and poor survival of CRC. ARF1 promoted colon tumorigenesis through its interaction with IQGAP1 and subsequent activation of ERK signaling and mitochondrial fission by enhancing the interaction of IQGAP1 with MEK and ERK. Mechanistically, azelastine bound to Thr-48 in ARF1 and repressed its activity, decreasing Drp1 phosphorylation. This, in turn, inhibited mitochondrial fission and suppressed colon tumorigenesis by blocking IQGAP1-ERK signaling. Conclusions: This study provides the first evidence that azelastine may be novel therapeutics for CRC treatment. ARF1 promotes colon tumorigenesis, representing a promising biomarker and therapeutic target in CRC.
RONC-21. IDENTIFICATION OF EPIGENETIC DRUGS AS RADIOSENSITIZERS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Dennis Metselaar, Giovanna ter Huizen, Michaël Hananja Meel, Joshua Goulding, Piotr Waranecki, Angel Montero Carcaboso, Gertjan Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2020)

Abstract Pediatric high-grade gliomas (pHGG) are malignant brain tumors with a high mortality rate. Radiotherapy (RT) is one of the cornerstones of current pHGG treatment, while the efficacy of chemotherapeutics remains inferior. The use of chemotherapeutics that specifically sensitize tumor cells to irradiation are poorly understood, but may help to increase the effect of RT in pHGG treatment. Since recent studies revealed pHGG to be epigenetically dysregulated, we tested 148 epigenetic drugs on eight primary pHGG models in the presence and absence of RT, to assess their radiosensitizing potential. Based on synergy scores, we found 22 compounds that resulted in enhanced cytotoxicity in the presence of RT. The effect of these compounds on pHGG was further investigated by tracking spheroid growth microscopically for 30 days, identifying four molecules that stopped spheroid-expansion solely in combination with RT (p=&amp;lt;0.001, multilevel regression). Parallel cell-viability assays reported identical results. Furthermore, tumor migration in 3D matrigel growth assays, using non-toxic doses of the four identified compounds, revealed that two compounds (the selective HDAC-inhibitors; chidamide and entinostat) stop the infiltrative growth characteristics of pHGG cells, exclusively in combination with RT. RNA-Seq data showed that entinostat and chidamide inhibit DNA-repair pathways like the Fanconi anemia cascade and homologous recombination. Since we anticipate that entinostat- or chidamide-induced radiosensitization can be enhanced by blocking kinase-driven escape mechanisms, we are currently conducting a kinome-wide CRISPR/Cas9 knockout screen in three primary pHGG models to develop combinational therapies. These results highlight entinostat and chidamide as potential radiosensitizers in pHGG treatment.
HGG-38. A COMPARATIVE PROTEOMIC-ANALYSIS OF THE CELL MEMBRANE FRACTIONS OF HISTONE 3 MUTATED BRAIN TUMOURS TO IDENTIFY NOVEL THERAPEUTICS
Authors: James Pickering, Ruman Rahman, Richard Grundy, Robert Layfield, Farhana Haque
Journal: Neuro-Oncology (2020)

Abstract Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome. We therefore analysed the cell surface proteomics of pHGG and DIPG, in order to identify novel targets for therapy. We have at first isolated the cell membrane fractions from a range of patient cells carrying different histone 3 mutations (G34R, G34V, K27M), relative to wild type histone 3. A comparative quantitative mass-spectrometry analyses of these cell surface membrane fractions is then performed to identify specific targetable factors, which can be then be used for tumour specific precision-therapy. Results of these experiments will be presented.
Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia
Authors: Kenichi Okuda, Hong Dang, Yoshihiko Kobayashi, Gianni Carraro, Satoko Nakano, Gang Chen, Takafumi Kato, Takanori Asakura, Rodney C. Gilmore, Lisa C. Morton, Rhianna E. Lee, Teresa Mascenik, Wei-Ning Yin, Selene Margarita Barbosa Cardenas, Yvonne K. O’Neal, Caroline E. Minnick, Michael Chua, Nancy L. Quinney, Martina Gentzsch, Carlton W. Anderson, Andrew Ghio, Hirotoshi Matsui, Takahide Nagase, Lawrence E. Ostrowski, Barbara R. Grubb, John C. Olsen, Scott H. Randell, Barry R. Stripp, Purushothama Rao Tata, Wanda K. O’Neal, Richard C. Boucher
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Identification of the specific cell types expressing CFTR (cystic fibrosis [CF] transmembrane conductance regulator) is required for precision medicine therapies for CF. However, a full characterization of CFTR expression in normal human airway epithelia is missing. Objectives: To identify the cell types that contribute to CFTR expression and function within the proximal–distal axis of the normal human lung. Methods: Single-cell RNA (scRNA) sequencing (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. scRNA in situ hybridization (ISH) and single-cell qRT-PCR were performed for validation. In vitro culture systems correlated CFTR function with cell types. Lentiviruses were used for cell type–specific transduction of wild-type CFTR in CF cells. Measurements and Main Results: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and, particularly, small airway superficial epithelia, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, whereas the expression in ciliated cells was infrequent and low. scRNA ISH and single-cell qRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to those of normal control subjects. CFTR mediated Cl− secretion in cultures tracked secretory cell, but not ionocyte, densities. Furthermore, the nucleotide–purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells and not with ionocytes. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl− secretion in CF airway secretory cells but not in ciliated cells. Conclusions: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.
DIPG-72. LONG-TERM SURVIVAL OF A CLASSIC DIFFUSE INTRINSIC PONTINE GLIOMA TREATED WITH NIMOTUZUMAB
Authors: Sidnei Epelman, Vijay Ramaswamy, Ethel Gorender, Luis Henrique Sakamoto
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Long-term survival in diffuse intrinsic pontine glioma is rare, and typically associated with atypical imaging and/or atypical clinical course. Although most patients harbor hotspot mutations in H3.1/3-K27M, a proportion of patients have alternate mutations, despite a typical clinicoradiological course. Herein we describe a long-term survivor with a classical presentation, treated with nimotuzumab, highlighting the challenges associated with such cases. CASE REPORT: A 5 year old male, diagnose in 2012 with a 10 day history multiple cranial neuropathies and a right hemiparesis. Cranial MRI revealed a poorly delimited diffuse pontine tumor and secondary hydrocephalus. Tumor biopsy was not performed due to the classic clinical presentation, and he received 54Gy/30 of radiation plus concomitant weekly nimotuzumab 150mg/m2. Initial tumor dimensions were 43x31x28mm. Nimotuzumab 150mg/m2 was continued every 2 weeks. Image assessment at week 12 of treatment revealed 16.9% volume increase, 4 weeks after radiotherapy completion. Nevertheless, subsequent neuroimaging at 24th, 36th, 60th, 96th and 108th weeks of nimotuzumab therapy showed a sustained and progressive tumor cytoreduction of 47.5%, 59%, 62.2%, 63.8% and 67%, respectively, when compared with post-radiotherapy dimensions. Currently, the patient is 13y old, good school performance, no neurologic disabilities. The last MRI at 394 weeks of nimotuzumab revealed dimensions of 21x19x14mm which corresponds to 70% of reduction compared with initial volume. CONCLUSIONS Our case of progressive cytoreduction over two years of a classic DIPG, diagnosed in the era prior to the discovery of the K27M mutation, highlights the challenges associated with long-term survival of this devastating entity.