bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Deep-Learning Approach for Inference of Selective Sweeps from the Ancestral Recombination Graph
Authors: Hejase Hussein A , Mo Ziyi , Campagna Leonardo , Siepel Adam 
Published: November 2021

AbstractDetecting signals of selection from genomic data is a central problem in population genetics. Coupling the rich information in the ancestral recombination graph (ARG) with a powerful and scalable deep-learning framework, we developed a novel method to detect and quantify positive selection: Selection Inference using the Ancestral recombination graph (SIA). Built on a Long Short-Term Memory (LSTM) architecture, a particular type of a Recurrent Neural Network (RNN), SIA can be trained to explicitly infer a full range of selection coefficients, as well as the allele frequency trajectory and time of selection onset. We benchmarked SIA extensively on simulations under a European human demographic model, and found that it performs as well or better as some of the best available methods, including state-of-the-art machine-learning and ARG-based methods. In addition, we used SIA to estimate selection coefficients at several loci associated with human phenotypes of interest. SIA detected novel signals of selection particular to the European (CEU) population at the MC1R and ABCC11 loci. In addition, it recapitulated signals of selection at the LCT locus and several pigmentation-related genes. Finally, we reanalyzed polymorphism data of a collection of recently radiated southern capuchino seedeater taxa in the genus Sporophila to quantify the strength of selection and improved the power of our previous methods to detect partial soft sweeps. Overall, SIA uses deep learning to leverage the ARG and thereby provides new insight into how selective sweeps shape genomic diversity.
Interstitial lung disease in a woman with rheumatoid arthritis treated with denosumab: A case report
Authors: Mori Yu , Izumiyama Takuya , Mori Naoko , Aizawa Toshimi 
Published: November 2021

ABSTRACT
The present report describes the case of an 84 year old female Japanese patient with rheumatoid arthritis (RA) who experienced exacerbation of interstitial lung disease (ILD) after denosumab (Dmab) treatment. The onset of RA occurred in 2008, and the patient had been treated with intravenous or subcutaneous injection of tocilizumab since 2009. In July 2013, she experienced a lumbar vertebral fracture and began treatment with 60 mg Dmab injection every 6 months in January 2014. The patient had a history of mild ILD and was evaluated for ILD by chest computed tomography (CT) imaging prior to the start of Dmab use. The vertebral fracture did not recur after the initiation of Dmab treatment, and her osteoporosis was successfully treated. However, she expressed a concern of exacerbations of cough and respiratory discomfort that had occurred since September 2019. The chest CT image in November 2015 showed minor ILD progression, whereas the image in September 2019 showed severe exacerbation of ILD. To treat this exacerbation, 10 mg of methylprednisolone and 2.5 mg of tacrolimus were administered, and Dmab was discontinued. The patient was subsequently switched to oral bisphosphonate. The patient’s respiratory discomfort and the finding of interstitial lung lesion in CT imaging improved after Dmab discontinuation. This case showed that exacerbation of ILD may occur after Dmab treatment, and physicians should consider the risks of Dmab-related ILD in patients with RA complicated by ILD.
A case of Paget’s disease of bone associated with hypomyopathic dermatomyositis
Authors: Soenjoyo Karina Ruth , Chua Marvin Wei Jie 
Published: November 2021

ABSTRACT
Dermatomyositis is associated with malignancies and is known to have systemic involvement. However, associations with bone diseases have not been well described in the current literature. This article describes the second reported case of the co-existence of dermatomyositis and Paget’s disease of bone (PDB), but this is the first report to describe such co-existence in a specific subtype of dermatomyositis—hypomyopathic dermatomyositis. Our patient was a 51 year old woman who presented with prolonged fever, myalgia, morning stiffness, and rashes pathognomonic of dermatomyositis. There was no muscle weakness clinically, although muscle enzymes were increased and electromyogram revealed myopathic changes. Further imaging showed the incidental finding of a T11 vertebral bone lesion, of which biopsy confirmed the diagnosis of PDB. Our report illustrates the diagnostic approach to bone lesions in patients with dermatomyositis and takes a closer look at the pathophysiology and management implications of the co-occurrence of these two rare diseases.
Database resources of the national center for biotechnology information
Authors: Sayers Eric W , Bolton Evan E , Brister J Rodney , Canese Kathi , Chan Jessica , Comeau Donald C , Connor Ryan , Funk Kathryn , Kelly Chris , Kim Sunghwan , Madej Tom , Marchler-Bauer Aron , Lanczycki Christopher , Lathrop Stacy , Lu Zhiyong , Thibaud-Nissen Francoise , Murphy Terence , Phan Lon , Skripchenko Yuri , Tse Tony , Wang Jiyao , Williams Rebecca , Trawick Barton W , Pruitt Kim D , Sherry Stephen T 
Published: November 2021

Abstract
The National Center for Biotechnology Information (NCBI) produces a variety of online information resources for biology, including the GenBank® nucleic acid sequence database and the PubMed® database of citations and abstracts published in life science journals. NCBI provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for the most of these databases. Resources receiving significant updates in the past year include PubMed, PMC, Bookshelf, RefSeq, SRA, Virus, dbSNP, dbVar, ClinicalTrials.gov, MMDB, iCn3D and PubChem. These resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.
NAD+ bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells
Authors: Li Jianfeng , M. Saville Kate , Ibrahim Md , Zeng Xuemei , McClellan Steve , Angajala Anusha , Beiser Alison , Andrews Joel F , Sun Mai , Koczor Christopher A , Clark Jennifer , Hayat Faisal , Makarov Mikhail V , Wilk Anna , Yates Nathan A , Migaud Marie E , Sobol Robert W 
Published: November 2021

Abstract
Elevated expression of the DNA damage response proteins PARP1 and poly(ADP-ribose) glycohydrolase (PARG) in glioma stem cells (GSCs) suggests that glioma may be a unique target for PARG inhibitors (PARGi). While PARGi-induced cell death is achieved when combined with ionizing radiation, as a single agent PARG inhibitors appear to be mostly cytostatic. Supplementation with the NAD+ precursor dihydronicotinamide riboside (NRH) rapidly increased NAD+ levels in GSCs and glioma cells, inducing PARP1 activation and mild suppression of replication fork progression. Administration of NRH+PARGi triggers hyperaccumulation of poly(ADP-ribose) (PAR), intra S-phase arrest and apoptosis in GSCs but minimal PAR induction or cytotoxicity in normal astrocytes. PAR accumulation is regulated by select PARP1- and PAR-interacting proteins. The involvement of XRCC1 highlights the base excision repair pathway in responding to replication stress while enhanced interaction of PARP1 with PCNA, RPA and ORC2 upon PAR accumulation implicates replication associated PARP1 activation and assembly with pre-replication complex proteins upon initiation of replication arrest, the intra S-phase checkpoint and the onset of apoptosis.
A robust confidence–accuracy dissociation via criterion attraction
Authors: Rahnev Dobromir 
Published: November 2021

Abstract
Many studies have shown that confidence and accuracy can be dissociated in a variety of tasks. However, most of these dissociations involve small effect sizes, occur only in a subset of participants, and include a reaction time (RT) confound. Here, I develop a new method for inducing confidence–accuracy dissociations that overcomes these limitations. The method uses an external noise manipulation and relies on the phenomenon of criterion attraction where criteria for different tasks become attracted to each other. Subjects judged the identity of stimuli generated with either low or high external noise. The results showed that the two conditions were matched on accuracy and RT but produced a large difference in confidence (effect appeared for 25 of 26 participants, effect size: Cohen’s d = 1.9). Computational modeling confirmed that these results are consistent with a mechanism of criterion attraction. These findings establish a new method for creating conditions with large differences in confidence without differences in accuracy or RT. Unlike many previous studies, however, the current method does not lead to differences in subjective experience and instead produces robust confidence–accuracy dissociations by exploiting limitations in post-perceptual, cognitive processes.
EPCO-04. RADIOTHERAPY IS ASSOCIATED WITH GLOBAL METHYLATION ALTERATIONS IN PATIENT DERIVED GLIOBLASTOMA CELL LINES
Authors: Modrek Aram , Byun David , Ezhilarasan Ravesanker , Snuderl Matija , Sulman Erik 
Published: November 2021

Abstract

PURPOSE/OBJECTIVE(S)
In glioblastoma, DNA methylation states are the most predictive marker of overall survival and response to therapy. Our understanding of how epigenetic states, such as DNA methylation, are “mis-repaired” after DNA damage repair is scant, hampering our ability to understand how treatment associated DNA methylation alterations may drive tumor resistance and growth.

MATERIALS AND METHODS
Three different patient derived IDH wild-type glioma stem cell (GSC) lines, in duplicates, were treated with radiation (20 Gray in 10 fractions vs. sham control) and allowed to recover prior to DNA methylation analysis with 850K methylation arrays. To analyze the methylation array data via bioinformatic methods we used RnBeads (version 2.4.0) and R (version 3.6.1) packages. We further focused our analysis to specific genomic regions, including CpG islands, promoters, gene bodies and CTCF motifs to understand how methylation alterations may differ between these and other genomic contexts following radiation.

RESULTS
There were widespread differential methylation (pre-treatment vs. radiation treatment) changes among the genomic regions examined. Interestingly, we found differential methylation changes at CTCF motifs, which play important DNA-methylation dependent roles in gene expression and chromatin architecture regulation. Hierarchical clustering, PCA and MDS analysis of DNA methylation status amongst CpG islands, promoters, gene bodies and CTCF domains revealed strong intra-sample differences, but not inter-sample differences (between GSC lines), suggesting radiation associated methylation alterations maybe loci and context dependent.

CONCLUSION
Radiation treatment is associated with wide-spread alterations of DNA methylation states in this patient derived glioblastoma model. Such alterations may drive gene expression changes or genomic architecture alterations that lead to treatment resistance, warranting further mechanistic investigation of the interplay between radiation induced DNA damage and local epigenetic state restoration following DNA damage repair.
EPCO-12. STING IS SILENCED IN GBM BY PROMOTER METHYLATION THAT IS ESTABLISHED BY TISSUE OF ORIGIN
Authors: Low Justin , Chandramohan Vidyalakshmi , Bowie Michelle , Brown Michael , Waitkus Matthew , Briley Aaron , Stevenson Kevin , Fuller Rebecca , Reitman Zachary , Muscat Andrea , hariharan Seethalakshmi , Hostettler Janell , Wong Nicholas , Gromeier Matthias , Ashley David M 
Published: November 2021

Abstract
STING (Stimulator of interferon genes) is an initiator of endogenous antitumor immunity. Loss of STING expression has been observed in various cancer types. Here we describe a mechanism of STING suppression that is common to brain tumors, occurring through regional promoter hypermethylation (RPH) near its transcriptional start site. The RPH-mediated suppression of STING expression is selective to normal brain and neuroectoderm-derived tumors, but not present in most other tumor types and cells in the brain tumor microenvironment. A pan-cancer comparison revealed that STING RPH levels in tumors correlate with the respective tissue of origin, including tumors metastasizing to the brain. We demonstrate that STING RPH suppression in glioma cells may be reversed by treatment with decitabine, a DNA methyltransferase inhibitor that is used in the treatment of hematologic malignancies. Collectively, our results suggest that the epigenetic silencing of STING occurs early in brain development and may provide an immunosuppressive context for the genesis of brain tumors. Furthermore, our findings that STING suppression in brain tumor cells can be reversed by epigenetic modulation have significant therapeutic implications for the treatment of glioblastoma and potentially other STING-silenced, immunologically-cold cancers.
EPCO-19. SYSTEMS BIOLOGY APPROACH ON MGMT-METHYLATED, IDH WILD-TYPE SHORT-TERM SURVIVORS REVEALS MUTATIONS IN THE BRCA1-MEDIATED DNA REPAIR SIGNALING PATHWAY
Authors: Noorbakhsh Cameron , Liu Yang , Lang Frederick , DeGroot John , Akdemir Kadir , Alfaro-Munoz Kristin , Parker-Kerrigan Brittany , Jaffray David , Huse Jason , Bhat Krishna , Puduvalli Vinay , Kannan Kasthuri 
Published: November 2021

Abstract
Numerous multi-omic studies have revealed the vast molecular complexity of glioblastoma; however, these studies have failed to identify actionable drivers for definitive therapy. Unlike conventional relational data analysis methods used to examine such data, systems biology approaches using graph databases have emerged as powerful tools with flexibility and scalability needed to reveal specific vulnerabilities. Here we demonstrate the utility of a patient-centric graph database in identifying novel factors associated with poor outcome (survival &lt; 8 months) in patients with MGMT promoter methylated glioblastoma. Using a cohort of 112 patients from the TCGA database, we integrated high-impact mutations with MGMT methylation status. Network analysis revealed three subnetworks, consisting of (a) methylated patients, the M-network, (b) methylated and unmethylated patients, the MU-network, and (c) unmethylated patients, the U-network. In addition, querying the genes in the M-network revealed three key molecules in the DNA repair pathway, namely, FANC-A, FANC-E, and MYUTH, mutated in five patients (q-value &lt; 2.3E-02). Moreover, we observed that BRCA1 mediates other critical signaling molecules in the MU-network. Interestingly, in intermediate (8-24 months) or long-term ( &gt;24 months) survivors networks, this pathway is not implicated. In light of recent studies implicating BRCA1 modulating temozolomide resistance in GBM sphere-forming cells and BRCA1’s protein expression predicting survival in patients, this result suggests that mutations in BRCA1-mediated DNA repair pathways hinder response to chemotherapy despite methylated MGMT, reducing the survival in patients. Besides this novel result explaining low survival in MGMT methylated patients through a synthesis of epigenetic and genetic data, our framework provides a novel and compelling paradigm for data integration at various scales from molecular events in a single patient’s tumor to integrating the molecular profile (or genotype) with phenotypic characteristics at the population level. We will present additional insights derived from this analysis at the SNO annual meeting.
EPCO-26. INTEGRATIVE MULTI-OMICS IDENTIFIES CONVERGING DEVELOPMENTAL ORIGINS OF DISTINCT MEDULLOBLASTOMA SUBGROUPS
Authors: Smith Kyle , Bihannic Laure , Gudenas Brian , Gao Qingsong , Haldipur Parthiv , Hovestadt Volker , Iskusnykh Igor , Chizhikov Viktor , Deng Mei , Glass Ian , Robinson Giles , Orr Brent , Patay Zoltan , Aldinger Kimberly , Millen Kathleen , Northcott Paul 
Published: November 2021

Abstract
Understanding the interplay between normal development and tumorigenesis, including the identification and characterization of lineage-specific origins of MB, is a fundamental challenge in the field. Recent studies have highlighted novel associations between biologically distinct MB subgroups and diverse murine cerebellar lineages via cross-species single-cell transcriptomics. Specifically, Group 4-MB correlated with the unipolar brush cell lineage and Group 3-MB resembled Nestin+ stem cells of the early cerebellum. However, these analyses were hampered by low resolution due to the sparsity of pertinent cerebellar cell types and the cross-species nature of the approach. Herein, we profoundly expand the depth of these rare developmental populations in the murine cerebellum using a combination of lineage tracing and integrative multi-omics. Isolation and enrichment of spatially and temporally unique developmental trajectories of key rhombic lip-derived glutamatergic lineages provided an enhanced reference for mapping MB subgroups based on molecular overlap, especially for poorly defined Group 3- and Group 4-MB. Further comparisons to a novel single-cell atlas of the human fetal cerebellum, companioned with laser-capture microdissected transcriptional and epigenetic datasets, reinforced developmental insights extracted from the mouse. Characterization of compartment-specific transcriptional programs and co-expression networks identified in the human upper rhombic lip implicated convergent cellular correlates of Group 3- and Group 4-MB, suggestive of a common developmental link. Together, our results strongly implicate developmental lineages of the upper rhombic lip as the probable origins of poorly defined Group 3- and Group 4-MB. These important findings will shape future efforts to accurately model the biological heterogeneity underlying these subgroups and provide unprecedented opportunities to explore their cellular and mechanistic basis.
BIOM-22. RELEVANCE OF TUMOR MUTATION BURDEN (TMB) IN HIGH-GRADE GLIOMAS
Authors: Ligumsky Hagai , Blumenthal Deborah , Bokstein Felix 
Published: November 2021

Abstract

BACKGROUND
Efforts have been directed toward searching for molecular biomarkers predicting response to immunotherapy in glial tumors. Recently, FDA granted accelerated approval of pembrolizumab for treatment patients with solid tumors with high mutational burden (TMB-H; ≥ 10 mut/Mb). There are conflicting results regarding the use of this parameter in glial tumors.

OBJECTIVE
to review NGS examinations of patients with glial tumors and high TMB and to analyze their response to immunotherapy.

METHODS
we retrospectively reviewed NGS examinations from patients with glial tumors treated in Tel-Aviv Medical Center from 2016-2021. Cases with TMB-H were retrieved and analyzed.

RESULTS
We identified nine high-grade glioma patients with TMB-H. The median age was 38 (19-65). There were 4 patients with glioblastoma; three with anaplastic oligodendroglioma; and two with anaplastic astrocytoma. All but one received radiation prior to the biopsy used for NGS examination, and all were treated with temozolomide. The median TMB was 54 (19-252). Only one glioblastoma patient with a family history of Lynch syndrome had microsatellite instability (MSI)-high; all other patients were MSI stable (MSS). Nevertheless, in all cases, mutated mismatch repair (MMR) genes were detected (MSH6 in 3 patients, MSH2 in one patient, MLH1 in one patient, PMS 2 in one patient, and both MSH2 and 6 in one patient). Six patients received immunotherapy. Only one patient with recurrent glioblastoma and the highest TMB in the group (252) demonstrated a near complete response to pembrolizumab and remains on treatment more than three years. All other patients did not respond to immunotherapy.

CONCLUSION
TMB-H in primary glioma is associated with mutations of MMR genes. It is typically associated with MSS in these patients (MSI-high was seen in only one syndromic patient). In contrast to systemic neoplasms with TMB-H, the majority of our patients did not respond to immunotherapy.
BIOM-27. INTEGRATED PREDICTION OF VENOUS THROMBOEMBOLISM IN GLIOMA PATIENTS
Authors: Unruh Dusten , Drumm Michael , Lamano Jonathan , Schwartz Margaret , Tran Anh , Javier Rodrigo , McCortney Kathleen , Amidei Christina , Burdett Kirsten , Scholtens Denise , Horbinski Craig 
Published: November 2021

Abstract

BACKGROUND
Venous thromboembolism (VTE) is a debilitating and life-threating condition that is common in patients with cancer, especially glioma. There are no widely-accepted guidelines for antithrombotic prophylaxis in glioma patients, in part because of the risk of iatrogenic intracerebral hemorrhage. Effective VTE prediction models exist for patients with other cancers, but not glioma. Our prior publications suggested a protective role of IDH mutation (IDHmut) against VTE, as well as a positive association between elevated circulating Tissue Factor (TF), a procoagulant secreted by cancers, and VTE in glioma patients. Others have recently found a correlation between podoplanin, a platelet activator, and cancer-associated VTE, but this has not yet been proven in gliomas. Our objective was to develop a multidimensional VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers.

METHODS
The Northwestern University Nervous System Tumor Bank provided preoperative arterial blood, tumor tissue, and clinical-pathologic data from 254 grade II-IV glioma patients over a 4-year interval. Molecular profiling was done by GlioSeq NGS.

RESULTS
Forty-six out of 254 grade II-IV glioma patients (18%) experienced VTE during their disease course. VTE was associated with worse median overall survival (18 vs. 54 months, P&lt; 0.001). Positive risk factors for VTE included advanced patient age, high body mass index, high glioma grade, prior history of VTE, coronary artery disease, hyperlipidemia, hypertension, and elevated circulating TF activity, among other variables. While tumor expression of podoplanin positively correlated with VTE, circulating podoplanin did not. Among molecular markers, the strongest was IDHmut, being associated with greatly reduced VTE risk (OR=0.28; 95% CI=0.12-0.64, P=0.001).

CONCLUSIONS
This study identified multiple risk factors for glioma-associated VTE. Using these data, we have developed a web-based multivariable integrated prediction calculator to identify glioma patients who would benefit the most from prophylactic anticoagulation.