tbuckley/cabot-search huggingface dataset:
Rolling-translated EGFR variants sustain EGFR signaling and promote glioblastoma tumorigenicity
Authors: Yi Liu, Zhongjun Li, Maolei Zhang, Huangkai Zhou, Xujia Wu, Jian Zhong, Feizhe Xiao, Nunu Huang, Xuesong Yang, Rong Zeng, Lixuan Yang, Zhibo Xia, Nu Zhang
Journal: Neuro-Oncology (2020)

Aberrant epidermal growth factor receptor (EGFR) activation is observed in over 50% of cases of adult glioblastoma (GBM). Nevertheless, EGFR antibodies are ineffective in clinical GBM treatment, suggesting the existence of redundant EGFR activation mechanisms. Whether circular RNA (circRNA) encodes a protein involved in EGFR-driven GBM remains unclear. We reported an unexpected mechanism in which circular EGFR RNA (circ-EGFR) encodes a novel EGFR variant to sustained EGFR activation.We used RNA-seq, Northern blot, and Sanger sequencing to confirm the existence of circ-EGFR. Antibodies and a liquid chromatograph tandem mass spectrometer were used to identify circ-EGFR protein products. Lentivirus-transfected stable cell lines were used to assess the biological functions of the novel protein in vitro and in vivo. Clinical implications of circ-EGFR were assessed using 97 pathologically diagnosed GBM patient samples.The infinite open reading frame (iORF) in circ-EGFR translated repeating amino acid sequences via rolling translation and programmed -1 ribosomal frameshifting (-1PRF) induced out-of-frame stop codon (OSC), forming a polymetric novel protein-complex, which we termed rolling-translated EGFR (rtEGFR). rtEGFR directly interacted with EGFR, maintained EGFR membrane localization and attenuated EGFR endocytosis and degradation. Importantly, circ-EGFR levels correlated with the EGFR signature and predicted the poor prognosis of GBM patients. Deprivation of rtEGFR in brain tumor-initiating cells (BTICs) attenuated tumorigenicity and enhanced the anti-GBM effect.Our findings identified the endogenous rolling-translated protein and provided strong clinical evidence that targeting rtEGFR could improve the efficiency of EGFR-targeting therapies in GBM.
CTNI-60. NEOAJUVANT CHEMOTHERAPY FOLLOWED BY CRANIOSPINAL IRRADIATION FOR INTRACRANIAL NGGCTS: CLINICAL OUTCOMES AND AGE-STRATIFIED TOXICITIES IN A COHORT OF 111 PATIENTS
Authors: Lei Wen, Juan Li, Mingyao Lai, Zhaoming Zhou, Qingjun Hu, Changguo Shan, Linbo Cai, Cheng Zhou
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Intracranial non-germinomatous germ cell tumors (NGGCTs) are rare tumors with limited studies available worldwide. Despite significantly improved survivals, there are still approximately 30% of patients experience relapse and require salvage treatment. This study aimed to access the clinical-pathological features and prognostic factors with specific interests to recurrence as well as adverse effects. METHODS From June 2005 and December 2018, 111 consecutive intracranial NGGCTs patients (87 localized stage and 24 metastatic stage) diagnosed based on histological confirmation, or alternatively by clinical presentation, radiological outcomes and elevated tumor markers were retrospectively analyzed. RESULTS After a median follow-up of 46.2 months, Three- and five- year OS were 83.5% ± 3.9% and 78.6% ± 5.1%, respectively. Three- and five- year EFS were 71.0% ± 4.8% and 64.7% ± 5.7%, respectively. Patients received craniospinal irradiation (CSI) integrated combined treatment yielded superior 3-year OS (P=0.007), EFS (P=0.002), and relapse rate (P=0.004) compared to those without CSI. A combination of minimum 4 cycles of induction chemotherapy and CSI integrated approach was the independent prognostic factor (P=0.007) conferring favorable 3-year OS and EFS of 93.9%±3.5% and 84.0%±5.4%, respectively. Poor prognosis of histological subtypes were particularly benefit from this treatment modality (P&amp;lt; 0.001). Age-thresholds for risking therapy-related thrombocytopenia and growth impairment by ROC analysis were 14 (AUC=0.752, P&amp;lt; 0.0001) and 11.5 (AUC=0.806, P&amp;lt; 0.01) yr., respectively. CONCLUSIONS Our study suggested that multimodal approach consisting of ≥4 cycles of induction chemotherapy and CSI plus focal boost with or without second-look surgery was recommended for NGGCTs. However, CSI should be used with caution when patients &amp;lt; 11.5-yr due to growth impairment. More precise risk stratifications are highly demanded for delivery of the most appropriate management in the future.
Galectin-9 expression defines exhausted T cells and impaired cytotoxic NK cells in patients with virus-associated solid tumors
Authors: Isobel Okoye, Lai Xu, Melika Motamedi, Pallavi Parashar, John W Walker, Shokrollah Elahi
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background We have previously reported that the upregulation of galectin-9 (Gal-9) on CD4 + and CD8 + T cells in HIV patients was associated with impaired T cell effector functions. Gal-9 is a ligand for T cell immunoglobulin and mucin domain-3, and its expression on T cells in cancer has not been investigated. Therefore, we aimed to investigate the expression level and effects of Gal-9 on T cell functions in patients with virus-associated solid tumors (VASTs). Methods 40 patients with VASTs through a non-randomized and biomarker-driven phase II LATENT trial were investigated. Peripheral blood mononuclear cells and tumor biopsies were obtained and subjected to immunophenotyping. In this trial, the effects of oral valproate and avelumab (anti-PD-L1) was investigated in regards to the expression of Gal-9 on T cells. Results We report the upregulation of Gal-9 expression by peripheral and tumor-infiltrating CD4 + and CD8 + T lymphocytes in patients with VASTs. Our results indicate that Gal-9 expression is associated with dysfunctional T cell effector functions in the periphery and tumor microenvironment (TME). Coexpression of Gal-9 with PD-1 or T cell immunoglobulin and ITIM domain (TIGIT) exhibited a synergistic inhibitory effect and enhanced an exhausted T cell phenotype. Besides, responding patients to treatment had lower Gal-9 mRNA expression in the TME. Translocation of Gal-9 from the cytosol to the cell membrane of T cells following stimulation suggests persistent T cell receptor (TCR) stimulation as a potential contributing factor in Gal-9 upregulation in patients with VASTs. Moreover, partial colocalization of Gal-9 with CD3 on T cells likely impacts the initiation of signal transduction via TCR as shown by the upregulation of ZAP70 in Gal-9+ T cells. Also, we found an expansion of Gal-9+ but not TIGIT+ NK cells in patients with VASTs; however, dichotomous to TIGIT+ NK cells, Gal-9+ NK cells exhibited impaired cytotoxic molecules but higher Interferon gamma (IFN-γ) expression. Conclusion Our data indicate that higher Gal-9-expressing CD8 + T cells were associated with poor prognosis following immunotherapy with anti-Programmed death-ligand 1 (PD-L1) (avelumab) in our patients’ cohort. Therefore, for the very first time to our knowledge, we report Gal-9 as a novel marker of T cell exhaustion and the potential target of immunotherapy in patients with VASTs.
RARE-12. VASCULOPATHY IN PEDIATRIC CRANIOPHARYNGIOMA PATIENTS TREATED WITH SURGERY AND RADIOTHERAPY
Authors: John Lucas, David LeVine, Yousef Ismael, Chi-Yang Hsu, Kaleb Darrow, Austin Faught, Vadim Moskvin, Fakhriddin Pilepesov, Noah Sabin, Frederick Boop, Paul Klimo, Lucas Elijovich, Thomas Merchant
Journal: Neuro-Oncology (2020)

Abstract PURPOSE As much as 40% of pediatric brain tumor patients will experience varied levels of Vasculopathy (VS), however few predictive factors have been described. Here we describe the type and timing of VS and explore the relationship between treatment modality and the timing, location, and distribution of VS. METHODS 94 pediatric Craniopharyngioma patients underwent surgery and proton radiotherapy. Pre- and post-treatment imaging, cumulative physical and biological proton dose maps, clinical characteristics, and measures of dyslipidemia were evaluated. MR and MRAs were evaluated for pre- and post-radiotherapy VS (type, workup, location, and severity). VS events were segmented and described according to their normal brain region, and vascular territory. RESULTS 47 patients were found to have 154 confirmed VS of varying severity with a median time to event of 3.41 years 95% CI 3.08–3.88. 22% (N=21) of patients had ≥1 pre-existing instances of VS and 26.6% (N=25) had a dyslipidemia at diagnosis. Forty-six (48.9%) patients had evidence of VS post-RT with 9.5% (N=9) being clinically significant. Aspirin was recommended in 10.6% (N=10) patients. Only 4 (4.2%) patients required revascularization. Clinical characteristics were not predictive of VS. An increased frequency of VS were observed along the operative corridor and high-dose radiotherapy field. CONCLUSIONS VS often precedes radiotherapy necessitating appropriate baseline imaging. Surgery type and extent are interrelated to the risk for radiotherapy-induced VS. While the spatial radiotherapy dose distribution approximated most vascular injury events, it was not all-inclusive. Spatial modeling of biological and physical dose may offer insights into therapy related vascular injury.
Abstract P434: Aortic Pulse Wave Velocity in Neonates: Feasibility and Comparison to Normative Data
Authors: Patricia Pagan Lassalle, Michelle L Meyer, Kim A Boggess, Lee Stoner
Journal: Circulation (2020)

Introduction: Cardiovascular disease (CVD) risk trajectory begins in early childhood and can be influenced by genetic and environmental factors. Carotid-femoral pulse wave velocity (cfPWV) is considered the gold standard for assessing CVD risk trajectory; however, there are no normative cfPWV data in children. Further, while cfPWV may be suitable for use in children, it is challenging in neonates. Brachial-femoral PWV (bfPWV), a less obtrusive measurement, may be an alternative method given the similar contours of carotid and brachial waveforms at this age. Our purpose was to: (a) use meta-regression to determine the normal rate of cfPWV progression in children, and (b) determine the feasibility of assessing bfPWV using an oscillometric technique in neonates. Hypothesis: We hypothesized that (a) cfPWV will increase with age, starting at birth, and (b) mean bfPWV values from neonates will overlap with the intercept (year 0) from the normative data generated from the meta-regression. Methods: Electronic databases were searched from inception to May 2018 for all studies in English that reported cfPWV in children (&lt;19 y) with at least 100 participants. Random effects meta-regression was used to quantify the association between time/age (years) and cfPWV. We measured bfPWV in 5 neonates (1-2 days old; mean weight 3.65 kg [SD: 0.52 kg]) using oscillometric cuffs, attached to the upper right arm and thigh, via the VICORDER ® . Results: We identified 9 studies for the meta-regression (3 longitudinal and 6 cross-sectional). The age of the participants ranged from 14.5 – 15.1 y in longitudinal studies, with a 2-5 y follow-up. The age range across the cross-sectional studies was 6-18 y. From the meta-regression, the increase in cfPWV per year (age) was 0.12 (95% CI: 0.07, 0.16) m/s. The cfPWV intercept (0 y) was 3.61 (95% CI: 3.07, 4.16) m/s. We successfully obtained acceptable quality bfPWV measurements on all neonates, with a mean bfPWV of 3.64 (95% CI: 3.31, 3.97) m/s. Conclusion: In children &lt;19 years old, cfPWV increases at a rate of 0.12 m/s per year. As hypothesized, mean values of bfPWV from the neonates overlap with the intercept from the meta-regression analysis. Evaluating bfPWV using an oscillometric technique is feasible and yields comparable results to published cfPWV data in children.
TBIO-12. THE SPECTRUM OF MITOCHONDRIAl DNA (mtDNA) MUTATIONS IN PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Kristiyana Kaneva, Petr Triska, Daria Merkurjev, Moiz Bootwalla, Jennifer Cotter, Dejerianne Ostrow, Katrina O’Halloran, Jaclyn Biegel, Xiaowu Gai
Journal: Neuro-Oncology (2020)

Abstract To explore the role of mitochondrial DNA mutations in pediatric CNS tumors, we analyzed 749 tumor-normal paired whole genome sequencing data sets from the Children’s Brain Tumor Tissue Consortium (CBTTC). We detected 307 somatic mtDNA mutations in 222 CNS tumors (29.6%). Most frequently observed were missense mutations (38.1%). We also detected 34 loss-of-function mutations. Different pediatric CNS tumor subtypes have distinct mtDNA mutation profiles. For categorical comparisons, we analyzed subtypes with at least 15 samples. The highest number of mtDNA mutations per tumor sample was in meningiomas (0.85), while atypical teratoid rhabdoid tumors (ATRTs) had the lowest number per sample (0.18). High-grade gliomas had a higher number of mtDNA mutations per sample than low-grade gliomas (0.56 vs. 0.31) (p = 0.0011), with almost twice as many missense mtDNA mutations per sample (0.22 vs. 0.13) (p &amp;lt; 0.001), and higher average heteroplasmy levels (11% vs. 9%). The average heteroplasmy was 10.1%, ranging from 15.6% in medulloblastoma to 6.36% in schwannoma suggesting that these are clonal alterations and not artifacts. Intriguingly, the two chordoma patients in the CBTTC database had an identical heteroplasmic m.10971G&amp;gt;A MT-ND4 nonsense mutation. Similarly, our patient with recurrent gliofibroma harbored the same somatic MT-ND4 synonymous variant (m.10700A&amp;gt;G) detected at 53% heteroplasmy in the initial tumor, 79% in the first recurrence, and 97% in the second recurrence. Although the functional consequences of these alterations are not yet understood, our findings suggest that sequencing the mtDNA genome may be used to characterize CNS tumors at diagnosis and monitor disease progression.
Identifying clinically extremely vulnerable people and asking them to shield should not be taken lightly
Authors: Carter Singh
Journal: BMJ (2020)

I agree that people in England who are clinically extremely vulnerable should receive a letter advising them to stay at home as much as possible, including not going to work if they cannot work at home, and only to leave the house to exercise outdoors or to attend health appointments.1 The letter needs to be easy to understand. The sender needs to take ownership and responsibility in dealing with questions. Recipients should not be signposted to general practice with their queries—there …
Abstract 12312: Mnk2 Kinase Promotes Cardiomyocyte Proliferation via Eif4e Phosphorylation in Mouse Heart After Myocardial Infarction
Authors: Bing-Rui Chen, Yi Fan, Ya-Fei Li, Hao Wang, Lian-Sheng Wang
Journal: Circulation (2019)

Introduction: Adult mice have limited potential for cardiac regeneration, and permanent damage to cardiomyocytes after cardiac injury leads to a decrease in cardiac contractile function. Conversely...
Biomarkers of inflammation and repair in kidney disease progression
Authors: Jeremy Puthumana, Heather Thiessen-Philbrook, Leyuan Xu, Steven G. Coca, Amit X. Garg, Jonathan Himmelfarb, Pavan K. Bhatraju, T. Alp Ikizler, Edward D. Siew, Lorraine B. Ware, Kathleen D. Liu, Alan S. Go, James S. Kaufman, Paul L. Kimmel, Vernon M. Chinchilli, Lloyd G. Cantley, Chirag R. Parikh
Journal: Journal of Clinical Investigation (2020)

INTRODUCTION. Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.
Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies
Authors: Jessica M. Franklin, Elisabetta Patorno, Rishi J. Desai, Robert J. Glynn, David Martin, Kenneth Quinto, Ajinkya Pawar, Lily G. Bessette, Hemin Lee, Elizabeth M. Garry, Nileesa Gautam, Sebastian Schneeweiss
Journal: Circulation (2020)

Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications.We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication.Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation.Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.
Abiola Olamide Aiyenigba
Authors: Andrew Weeks
Journal: BMJ (2020)

Abiola Olamide Aiyenigba (nee Adelowo) was born on 2 September 1977 in London but moved to Nigeria as a baby, where she attended Mayflower Junior School in Ogun State and Federal Government Girls College, Sagamu, for her secondary school education. She studied food science and technology, then medicine at Olabisi Onabanjo University, Ago-Iwoye. After her graduation she returned to the UK, where she met …
Definition of a Prognostic Risk-Classifier Based on SNPs Array Analysis of Copy Number Alterations in Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients
Authors: Carolina Terragna, Vincenza Solli, Andrea Poletti, Barbara Santacroce, Marina Martello, Alessandra Larocca, Luca Dozza, Anna Baraldi, Lucia Pantani, Adelina Sementa, Paola Tacchetti, Norbert Pescosta, Elena Zamagni, Giovanna Leonardi, Caterina Musolino, Giulia Marzocchi, Letizia Canepa, Gaia Ameli, Beatrice Zannetti, Anna Pascarella, Enrica Borsi, Luca De Rosa, Nicoletta Testoni, Giovanni Martinelli, Pieter Sonneveld, Michele Cavo
Journal: Blood (2017)
Publisher Correction: Macro and micro sleep architecture and cognitive performance in older adults
Authors: Ina Djonlagic, Sara Mariani, Annette L. Fitzpatrick, Veerle M. G. T. H. Van Der Klei, Dayna A. Johnson, Alexis C. Wood, Teresa Seeman, Ha T. Nguyen, Michael J. Prerau, José A. Luchsinger, Joseph M. Dzierzewski, Stephen R. Rapp, Gregory J. Tranah, Kristine Yaffe, Katherine E. Burdick, Katie L. Stone, Susan Redline, Shaun M. Purcell
Journal: Nature Human Behaviour (2020)
Assessment of an Online Tool to Simulate the Effect of Pooled Testing for SARS-CoV-2 Detection in Asymptomatic and Symptomatic Populations
Authors: Christopher R. Polage, Mark J. Lee, Christopher Hubbard, Catherine Rehder, Diana Cardona, Thomas Denny, Michael B. Datto
Journal: JAMA Network Open (2020)

This diagnostic study describes an online tool created with actual severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus copy number data to help policy makers understand how pooled testing compares with single-sample testing in different populations.
NIMG-29. DEVELOPING AUTOMATIC SEGMENTATION METHOD FOR BRAIN TUMOR MR IMAGES THAT CAN BE USED AT MULTIPLE FACILITIES
Authors: Satoshi Takahashi, Masamichi Takahashi, Manabu Kinoshita, Mototaka Miyake, Risa Kawaguchi, Naoki Shinojima, Akitake Mukasa, Kuniaki Saito, Motoo Nagane, Ryohei Otani, Keisuke Ueki, Shota Tanaka, Nobuhiro Hata, Ryo Nishikawa, Hideyuki Arita, Masahiro Nonaka, Kaoru Tamura, Kensuke Tateishi, Takehiro Uda, Junya Fukai, Yoshiko Okita, Naohiro Tsuyuguchi, Yonehiro Kanemura, Kazuma Kobayashi, Jun Sese, Kouichi Ichimura, Yoshitaka Narita, Ryuji Hamamoto
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Manual segmentation of brain tumor images from a large volume of MR images generated in clinical routines is difficult and time-consuming. Hence, it is imperative to develop a machine learning model for automated segmentation of brain tumor images. PURPOSE Machine learning models for automated MR image segmentation of gliomas may be useful. However, the image differences among facilities cause performance degradation and impede successful automatic segmentation. In this study, we proposed a method to solve this issue. METHODS We used the data from the Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) and the Japanese cohort (JC) datasets collected from 10 facilities. Three models for tumor segmentation were developed. The BraTS model was trained on the BraTS dataset, and the JC model was trained on the JC dataset; whereas, the Fine-tuning model was a fine-tuned BraTS model using the JC dataset. RESULTS MR images of 544 patients were obtained for the JC dataset. Half of the JC dataset was used for independent testing. The Dice coefficient score of the JC model for the JC dataset was 0.779± 0.137, whereas that of the BraTS model was remarkably lower (0.717 ± 0.207). The mean of the Fine-tuning models for the JC dataset was 0.769 ± 0.138. There was a significant difference between the BraTS and JC models (P &amp;lt; 0.0001) and the BraTS and Fine-tuning models (P = 0.002); however, no significant difference was observed between the JC and Fine-tuning models (P = 0.673). CONCLUSIONS Application of the BraTS model to heterogeneous datasets can significantly reduce its performance; however, fine-tuning can solve this issue. Since our fine-tuning method only requires less than 20 cases, this methodology is particularly useful for a facility where there are a few glioma cases.
Comparative proteomics of common allergenic tree pollens of birch, alder, and hazel
Authors: Barbara Darnhofer, Tamara Tomin, Laura Liesinger, Matthias Schittmayer, Peter Valentin Tomazic, Ruth Birner‐Gruenberger
Journal: Allergy (2020)

In addition to known allergens, other proteins in pollen can aid the development of an immune response in allergic individuals. The contribution of the "unknown" protein allergens is apparent in phylogenetically related species where, despite of high homology of the lead allergens, the degree of allergenic potential can vary greatly. The aim of this study was to identify other potentially allergenic proteins in pollen of three common and highly related allergenic tree species: birch (Betula pendula), hazel (Corylus avellana) and alder (Alnus glutinosa).