tbuckley/cabot-search huggingface dataset:
CSIG-28. LONG NONCODING RNA MIR22 HOST GENE-DERIVED miR-22-3p AND miR-22-5p PROMOTE PROLIFERATION, INVASION AND SELF-RENEWAL IN HUMAN GLIOMAS VIA Wnt/-CATENIN SIGNALING
Authors: Mingzhi Han, Shuai Wang, Jian Wang, Xingang Li, Rolf Bjerkvig
Journal: Neuro-Oncology (2018)

Long noncoding RNAs (lncRNAs) are essential transcripts with critical roles in tumor initiation and malignant progression. In the present study, through analysis of whole-transcriptome profiles, we showed that MIR22 host gene (MIR22HG), the primary microRNA of miR-22, ranked among the most overexpressed lncRNAs in glioblastoma (GBM). Herein, our study aims to elucidate the biological functions of MIR22HG and therapeutic potency of MIR22HG targeted inhibition in GBM. We characterized the expression pattern of MIR22HG/miR-22 by bioinformatics analysis and by in situ hybridization (ISH) in GBMs. We further determined whether genetic targeting of MIR22HG affected oncogenic functions of primary GBM cells in vitro and in vivo. A co-culture model where brain organoids are co-cultured with GBM spheroids were utilized for the invasion assessment. Finally, based on the three-dimensional structure of the pre-miR-22, we performed virtual screening strategy to disclose a novel inhibitor of the MIR22HG/miR-22 axis. We showed that MIR22HG/miR-22 was highly expressed in GBM, especially in isocitrate dehydrogenase 1/2 (IDH1/2) wild-type tumors. Specially, MIR22HG/miR-22 was preferentially expressed in glioblastoma stem cells (GSCs) compared to normal neural stem cell (NSCs). Analysis of intra-tumoral transcriptional heterogeneity showed that MIR22HG was higher in the infiltrating region compared to the tumor center. In functional assays, silencing MIR22HG attenuated aggressive phenotypes in GBM cells, including invasion, self-renewal and in vivo tumor growth via suppressing the production of miR-22-3p and miR-22-5p. Using a luciferase reporter assay, we further confirmed that two inhibitors of the Wnt/β-catenin pathway, SFRP2 and PCDH15, were direct targets of miR-22-3p and miR-22-5p. Finally, we identified a specific inhibitor termed AC1L6JTK, which blocks the ability of Dicer to process pre-miR-22 to mature miR-22, thus exerting therapeutic efficacy on GBMs. Our findings show that the MIR22HG/miR-22 axis is a novel biomarker as well as a therapeutic target in GBM.
Abstract 14972: Sub-clinical Atrial Fibrillation in Elderly Primary Care Patients Without Clinical Atrial Fibrillation
Authors: Jeff S Healey, Stuart J Connolly, Veena Manja, Yan Liu, Kim D Simek, Russell Quinn, Roopinder K Sandhu, Noah Ivers, David J Gladstone
Journal: Circulation (2015)

Introduction: Sub-clinical AF has been reported in 10% of pacemaker patients (≥ 6 minutes, with 3 months of monitoring) and 16% of patients following cryptogenic stroke (≥ 30 seconds, with 1 month of monitoring). It is unknown how common sub-clinical AF is among other patient groups, including the elderly. These data are needed to give context to the detection of sub-clinical AF in clinical practice. Methods: We prospectively investigated the prevalence of sub-clinical AF among individuals ≥ 80 years, without known AF or symptoms of arrhythmia, attending primary care clinics. Subjects had a history of hypertension and at least one of the following: diabetes, BMI ≥ 30, sleep apnea, smoking, coronary disease, heart failure or left ventricular hypertrophy. Patients were recruited from 7 Ontario family practice clinics (n=119) and one general medicine clinic (n=10). Patients underwent 30 days of continuous, non-invasive ambulatory ECG monitoring using a device with automatic AF detection (Vitaphone 3100). The primary outcome was a composite of atrial flutter (AFL) or AF ≥ 6 minutes in duration. Those without AF were invited to complete an additional 30 days of monitoring. Results: Of 129 patients screened and consented, 100 patients initiated monitoring for an average monitoring duration of 36± 21 days. The mean (SD) age was 84 ± 3 years and systolic blood pressure was 138 ± 17 mmHg; 50% had coronary disease, 28% had diabetes and 6% had heart failure. Only 4% had a history of prior stroke. Thirty days of monitoring was completed by 57% of patients and 31% completed an additional 30 days. AFL or AF ≥ 30 seconds duration was documented in 19/100 patients; ≥ 6 minutes in 15; ≥ 30 minutes in 12; ≥ 6 hours in 8 and ≥ 24 hours in 2. Shorter episodes of atrial tachycardia lasting less than 30 seconds were observed in 47 patients. Conclusions: In this prospective, outpatient study, using non-invasive ECG monitoring, we found AFL or AF ≥ 6 minutes in 15% of elderly individuals with stroke risk factors. This high background prevalence of AFL/AF among elderly patients suggests a possible role for AF screening in this population; but also should be taken into consideration when interpreting the prevalence of AFL/AF in other populations.
INNV-10. PERIPHERAL MYELOID CELL pd-l1 IS A BIOMARKER FOR HIGH-GRADE INTRACRANIAL MALIGNANCY
Authors: Yuping Li, Jonathan Lamano, Joseph DiDomenico, Dauren Biyashev, Dorina Veliceasa, Gurvinder Kaur, Jason Lamano, Orin Bloch
Journal: Neuro-Oncology (2018)

Immunosuppression is a hallmark feature of primary and metastatic malignancies in the brain. Expansion of suppressive myeloid cells expressing PD-L1 has been demonstrated in circulation of GBM patients. Similar findings have been reported in numerous advanced malignancies, but the presence of suppressive myeloid cells is rarely seen in patients with benign tumors. We hypothesized that expression of PD-L1 on peripheral myeloid cells may be used to differentiate malignant from non-malignant brain tumors prior to tissue diagnosis. Peripheral blood was collected from 189 patients undergoing surgical resection of tumors, including low grade gliomas (n=5), high grade gliomas/GBM (n=76), benign meningiomas (n=18), atypical meningiomas (n=25), anaplastic meningiomas (n=10), non-metastatic early stage NSCLC (n=15), and brain-metastatic NSCLC (n=34), as well as from healthy donors (n=6). Immunosuppressive myeloid cells (CD45+CD11b+CD163+/-PD-L1+) and myeloid-derived suppressor cells (MDSCs) (CD11b+CD33+HLA-DRloPD-L1+/-) were quantified through flow cytometry. Peripheral myeloid PD-L1 positivity was significantly elevated in patients with high grade vs. low grade gliomas (19.7% vs. 5.7%; p<0.0001), anaplastic vs. other meningiomas (12.6% vs. 6.2%; p<0.01), and brain-metastatic vs. non-metastatic NSCLC (11.3% vs. 4.1%; p<0.0001). Using a threshold of 10%, peripheral monocyte PD-L1 expression was found to be predictive of high grade malignancy with a positive predictive value of 95.2%. Sensitivity was 57.1% and specificity was 96.2%. MDSC abundance was also significantly increased in patients with high grade tumors (36.3% in gliomas, 14.4% in meningiomas, 18.0% in metastatic NSCLC) compared to lower grade tumors (11.4%) and healthy donors (5.7%). Expansion of PD-L1+ myeloid cells is strongly associated with the presence of intracranial malignancy, with a predictive value in excess of 95% for patients with an intracranial mass. In cases where pre-biopsy knowledge of a high-grade malignancy may change the surgical approach to diagnosis and treatment, blood analysis for myeloid PD-L1 may be considered as a first step.
NIMG-23. DEEP LEARNING FOR ACCURATE, RAPID, FULLY AUTOMATIC MEASUREMENT OF BRAIN TUMOR-ASSOCIATED ABNORMALITY SEEN ON MRI
Authors: Joseph Mitchell, Konstantinos Kamnitsas, Kyle Singleton, Scott Whitmire, Kamala Clark-Swanson, Cassandra Rickertsen, Ben Glocker, Leland Hu, Kristin Swanson
Journal: Neuro-Oncology (2018)

Brain tumors are difficult to segment in MRI scans. Consequently, we have developed a new system for completely automatic brain tumor segmentation by combining a state-of-the-art 3D deep convolutional neural network (CNN) with a large collection of curated segmentations of brain tumors. Our brain tumor database holds 74,722 MRI series from 2,742 unique patients. Over the last 15 years our image analysis team has segmented brain tumors in 35,710 of these series. This preliminary experiment identified 741 pre-treatment studies that included a T1GD and FLAIR scan, and at least one adjudicated brain tumor segmentation. These studies were randomly assigned into 600 training, 41 validation, and 100 test cases. CNN training was performed in two stages: 1) 50 epochs on minimally modified MRI volumes; and, 2) 24 epochs to tune the CNN on skull-stripped volumes. Whole-tumor Dice coefficients (1=perfect overlap, 0=no overlap) were calculated by comparing CNN segmentations against adjudicated segmentations from trained measurers. Training was performed in-the-cloud using an Amazon Machine Instance equipped with an NVidia Tesla V100 GPU, 8 Intel Xeon processors, and 64 GB of RAM. Training required 74 hours. Afterwards, our network required 800 seconds to segment 100 studies in the test set (8 seconds/study). The mean whole-tumor Dice coefficient on the test studies was 0.885. DISCUSSION: The best result on the highly cited 2017 BraTS brain tumor segmentation challenge was a whole-tumor Dice of 0.886, achieved by an ensemble of 7 CNNs. BraTS included 274 studies, each with T1GD, FLAIR, T1 and T2 contrasts. The performance of our single CNN may be due to our comparatively large training set. Our goal is to train our CNN on all series in our database. This may provide useful tools to monitor each patients journey, from diagnosis through treatment.
ANGI-07. 5ALA FLUORESCENCE BASED SORTING IDENTIFIES SERPINE1 AS A NOVEL THERAPEUTIC TARGET ON INVASIVE GBM CELLS
Authors: Jonathan Rowlinson, Maria de los Angeles Estevez Cebrero, Anbarasu Lourdusamy, Ruman Rahman, Stuart Smith
Journal: Neuro-Oncology (2018)

INTRODUCTION: We previously described separating invasive tumor cells from within normal brain using 5ALA based fluorescent activated cell sorting (FACS). Using RNAseq on these cells we identify new potential therapeutic targets whose expression is elevated in tumor cells invading brain parenchyma. METHOD: 5-aminolevulinic acid (5-ALA) is a clinically used drug for fluorescence guided resection of GBM. Tumors from 11 patients were dissociated and FACS used to separate invasive fluorescent cancer cells from within normal brain. FACS sorted and unsorted mixed samples from tumor core, rim and invasive margin were compared. Gene expression was analyzed by RNA-seq and validated by qPCR, IHC and in vivo xenografts. Differential expression analysis identified 2567 genes with differences between core and invasive margin, and 78 genes with differences between 5-ALA FACS positive and FACS negative. Interestingly SERPINE1 expression is reduced in the unsorted invasive margin but expression remains high within sorted invasive tumor cells. Pathway analysis identified a predominance of immune system pathway changes between core and invasive margin. The differential expression of SERPINE1, VEGF, CHI3L1 and RTN1 in qPCR and IHC validated the same changes observed from the RNA-seq data. The invasive and tumorigenic capacity of 5-ALA positive sorted tumor cells was confirmed by enhanced engraftment in a mouse flank model compared to unsorted cells, whereas 5-ALA negative sorted cells failed to engraft. SERPINE1 knockdown had no effect on GBM cell proliferation but significantly reduced the ability of GBM cells to invade in an in vitro assay. CONCLUSION: This study has demonstrated that 5-ALA fluorescent sorting of the invasive region can identify new targets such as SERPINE1, whose high expression in invasive tumor cells would otherwise be overlooked. Our approach gives hope that we can interrogate true residual disease, identifying more relevant therapeutic targets.
RTHP-13. TUMOR-TREATING FIELDS THERAPY IS COMPATIBLE WITH STANDARD CHEMORADIOTHERAPY FOR GLIOBLASTOMA
Authors: Gregory Stachelek, Jimm Grimm, Michael Lim, Chetan Bettegowda, Kristin Redmond, Lawrence Kleinberg
Journal: Neuro-Oncology (2018)

PURPOSE: The phase III EF-14 trial demonstrated a significant overall survival benefit in 695 patients with glioblastoma who received adjuvant anti-mitotic tumor-treating fields (TTFields) therapy in addition to temozolomide (TMZ), following standard concurrent radiotherapy (RT) and TMZ. Preclinical studies suggest that there may be an added synergistic benefit to TTFields when used concurrently with RT. We therefore conducted dosimetric analyses to assess whether the presence and repositioning of TTFields scalp arrays interferes with RT delivery and to evaluate implications for treatment planning. RT plans from ten consecutive glioblastoma patients at our institution were transferred to an anthropomorphic cranial phantom and re-optimized using standard tumor and normal tissue constraints. Optimized plans were then copied to CT scans of the phantom wearing the TTFields array in three discrete positions, to simulate routine replacement of the array in clinical use. Individual and average perturbations to RT dosimetry for each plan/array combination were then analyzed. The percent change in planning target volume (PTV) coverage for each of the 30 combinations ranged from -3.0% to 1.1%. When averaged over the three array positions, PTV coverage for each patient had standard deviation of less than 1.0%. Changes in PTV coverage were attributable to attenuation by the array and increased superficial dose owing to bolus effect. Percent increase in radiation dose to skin was 5.0% or less in 9 out of 10 plans. The dosimetric impact of the TTFields arrays for any individual position is small and is further mitigated by repositioning of the arrays as would occur during chemoradiation. These dosimetric changes were consistent across varied tumor location, laterality, and RT beam arrangement in our patient cohort. We are initiating a clinical trial to test safety and develop procedures for the use of TTFields during chemoradiotherapy for glioblastoma.
Abstract 15986: Comparative Outcomes in Marfan and Non-Marfan Aortopathy
Authors: Richmond Jeremy, Andrew Sherrah, Sarah Andvik
Journal: Circulation (2012)

Heritable aortopathy causes thoracic aneurysm and dissection (TAAD) in younger adults and survival predictors are likely to differ from older hypertensive disease. From 1988 to 2011, 211 Marfan (re...
Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy
Authors: Markus Burkard, Susanne Kohl, Timm Krätzig, Naoyuki Tanimoto, Christina Brennenstuhl, Anne E. Bausch, Katrin Junger, Peggy Reuter, Vithiyanjali Sothilingam, Susanne C. Beck, Gesine Huber, Xi-Qin Ding, Anja K. Mayer, Britta Baumann, Nicole Weisschuh, Ditta Zobor, Gesa-Astrid Hahn, Ulrich Kellner, Sascha Venturelli, Elvir Becirovic, Peter Charbel Issa, Robert K. Koenekoop, Günther Rudolph, John Heckenlively, Paul Sieving, Richard G. Weleber, Christian Hamel, Xiangang Zong, Martin Biel, Robert Lukowski, Matthias W. Seeliger, Stylianos Michalakis, Bernd Wissinger, Peter Ruth
Journal: Journal of Clinical Investigation (2018)

Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide–gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype ranging from complete and incomplete achromatopsia to moderate cone dysfunction or progressive cone dystrophy. By exploring a large patient cohort and published cases, we identified 16 unrelated individuals who were homozygous or (compound-)heterozygous for the CNGB3/c.1208G>A;p.R403Q mutation. In-depth genetic and clinical analysis revealed a co-occurrence of a mutant CNGA3 allele in a high proportion of these patients (10 of 16), likely contributing to the disease phenotype. To verify these findings, we generated a Cngb3R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3–/–) mice to obtain triallelic Cnga3+/– Cngb3R403Q/R403Q mutants. As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice. These findings strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation, with important implications for diagnosis, prognosis, and genetic counseling.
Incidence Trends of Atopic Dermatitis in Infancy and Early Childhood in a Nationwide Prescription Registry Study in Norway
Authors: Cathrine H. Mohn, Hege Salvesen Blix, Jon Anders Halvorsen, Per Nafstad, Morten Valberg, Per Lagerløv
Journal: JAMA Network Open (2018)

Importance With increasing prevalence of atopic dermatitis (AD) and its manifestation in most countries, together with the supporting evidence of the progression to other atopic phenotypes, AD has developed into a worldwide public health concern. The presence of the disease of has increased since the 1950s, but some recent studies suggest a stationary or decreasing trend. Objective To analyze a nationwide health register based on prescription data to determine the incidence rate (IR) of AD in an entire pediatric population. Design, Setting, and Participants All children resident in Norway younger than 6 years from January 1, 2009, through December 31, 2015, were included in this cohort study. Medical diagnoses and disease-specific medications were used as a proxy for identifying children with AD in this population-based prescription registry study. The prescription study was terminated in 2016. The total number of 295 286 disease-specific prescriptions was analyzed from August 2016 through December 2017. The hypothesis was formulated before, during, and after the data collection. Main Outcomes and Measures All children with a medical diagnosis of AD or eczema based on at least 2 prescriptions of topical corticosteroids or at least 1 prescription of topical calcineurin inhibitors. Incidence rates per person-year (PY) and IR ratios were calculated. Results A total of 295 286 disease-specific prescriptions were dispensed to 122 470 children, of whom 63 460 had AD and 56 009 (88.3%) had reimbursed prescriptions and associated AD diagnoses. The annual Norwegian study population (aged &amp;amp;lt;6 years) increased from 357 451 children in 2009 to 373 954 in 2015. The overall IR increased from 0.028 per PY (95% CI, 0.028-0.029 per PY) in 2009 to 0.034 per PY (95% CI, 0.033-0.035 per PY) in 2014. For children younger than 1 year, the IR increased from 0.052 per PY (95% CI, 0.050-0.053 PY) in 2009 to 0.073 per PY (95% CI, 0.071-0.075 per PY) in 2014. In this age group, the IR was 53% higher in boys compared with girls (IR ratio, 1.53; 95% CI, 1.49-1.57; P &amp;amp;lt; .001). The incidence proportion before the age of 6 years was 17.4% (95% CI, 17.2%-17.7%). The primary seasons for the onset of AD were winter and spring. Conclusions and Relevance This nationwide study suggests an increase in the IR of pediatric AD, especially among children younger than 1 year. This study’s findings suggest that increase occurred with a higher IR during winter and spring seasons. Atopic dermatitis had an earlier onset in boys than in girls. During the study period, more than 1 in 6 children younger than 6 years had, at some point, been affected by AD.
STEM-10. MOLECULAR MECHANISMS UNDERLYING PHENOTYPIC PLASTICITY IN MALIGNANT GLIOMA
Authors: Costanza LoCascio, Ernesto Luna-Melendez, Shwetal Mehta
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is characterized by rapidly proliferating and invasive cells that infiltrate normal brain regions. Following exposure to aggressive treatment regimens, GBMs frequently shift their biological features upon recurrence, acquiring a more resistant phenotype. However, the dynamics and molecular mechanisms that facilitate GBM recurrence are still poorly understood. The objective our study was to determine how glioma stem cells (GSCs) temporally adjust their expression profile and phenotype in response to ionizing radiation or Temozolomide (TMZ) in vivo using patient-derived xenograft (PDX) models of GBM. We established two PDX GBM models by intracranially implanting two patient-derived GSC lines belonging to different GBM molecular subgroups (proneural and classical) into immunocompromised mice. The tumor-bearing mice were treated with single or multiple doses of ionizing radiation or TMZ to assess acute and long-term responses to treatment respectively. Mice from each cohort were be sacrificed at multiple distinct time points following treatment. Using immunohistochemical methods, we assessed changes in the expression of GBM subclass markers, stemness and differentiation markers, and DNA damage/repair proteins across the entire tumor population over time. Furthermore, to understand how the PDX tumors respond to radiation at a molecular level, we employed mass cytometry (CyTOF) and ChIP-seq to determine how important cellular signaling pathways and transcriptional programs necessary for GSC self-renewal, invasion and growth are altered at various time points post-treatment. We demonstrate that GSCs undergo an immediate response following exposure to radiation that results in a global modulation of the expression of key stemness and proliferation genes under adverse conditions. Our results suggest that this acute response allows GSCs to enter a transient semi-differentiated state that favors GSC adaptability and resistance to therapy.
EPID-05. A CASE SERIES OF METASTATIC GLIOBLASTOMA AT MEMORIAL SLOAN KETTERING CANCER CENTER
Authors: Evan Noch, Sameer Sait, Alexandra Miller
Journal: Neuro-Oncology (2018)

Extracranial metastasis of glioma is a rare event during the progression of this type of brain tumor, often occurring in patients with advanced disease. Though intracranial glioblastoma continues to carry a poor prognosis, extracranial metastasis is a particularly unfavorable factor in survival. We present a case series of 7 patients at Memorial Sloan Kettering Cancer Center from 2003 to 2018 with metastatic extracranial glioblastoma or gliosarcoma. 5 patients had glioblastoma, 1 patient had gliosarcoma, and 1 patient had ganglioglioma that progressed to gliosarcoma. The age of these patients at diagnosis ranged from 14 to 73, with 6 men and 1 woman in this group. The median overall survival from initial diagnosis and from diagnosis of extracranial metastasis was 13.2 (range 9.2–37.6) and 5 (range 1–6) months, respectively. The most common site of extracranial metastatic disease was bone, with other sites being cervical and thoracic lymph nodes, liver, lung, and soft tissues. 5 patients had symptoms referable to their site of extracranial metastasis, with the most common symptoms being pain and shortness of breath. All patients received initial surgical resection, followed by radiation and temozolomide, with subsequent chemotherapeutic regimens administered that were most appropriate for their individual cases. 1 patient had an Ommaya placed during the course of his illness, 1 patient had a craniectomy for severe cerebral edema, and 2 other patients had dural-based disease. These cases demonstrate several potential risk factors for extracranial metastasis of glioblastoma and gliosarcoma, namely disruption of normal anatomic barriers during surgical resection, intraventricular catheter placement, and sarcomatous dedifferentiation. Next steps with this work include further analysis of the molecular features of extracranial glioblastoma metastases with respect to the site of primary disease, which we anticipate will lead to a better understanding of the molecular mechanisms of metastasis and may improve treatments for these patients.