bluuebunny/crossref_metadata_2025_split huggingface dataset:
Controlling Voices in Fourteenth-Century Salzburg: Singing and Identity in the ‘MÖnch von Salzburg’ Songs
Authors: Murray David 
Published: August 2022

ABSTRACT
The songs attributed to the so-called ‘Mönch von Salzburg’ offer a vivid picture of the late fourteenth-century ecclesiastical court of Archbishop Pilgrim von Pucheim. Against the background of historical and legal documentation from Salzburg, this article explores the way these songs negotiate the desires and anxieties of a mixed clerical-courtly milieu with a particular concern for regulating the human voice in both artistic and social senses. Taking as my central example Dy trumpet, one of the earliest pieces of recorded secular polyphony in the German world, I examine how both the singing and composition of song at Pilgrim’s court offered ways to certify one’s vocal interventions as positive and thereby to assure curial kudos. In a final section, I consider how later, non-curial recipients of these songs were able to vehicularize these courtly voices to their own advantage.
Observational signatures of stellar explosions driven by relativistic jets
Authors: Eisenberg Moshe , Gottlieb Ore , Nakar Ehud 
Published: August 2022

ABSTRACT
The role of relativistic jets in unbinding the stellar envelope during a supernova (SN) associated with a gamma-ray burst (GRB) is unclear. To study that, we explore observational signatures of stellar explosions that are driven by jets. We focus on the final velocity distribution of the outflow in such explosions and compare its observational imprints to SN/GRB data. We find that jet-driven explosions produce an outflow with a flat distribution of energy per logarithmic scale of proper velocity. The flat distribution seems to be universal as it is independent of the jet and the progenitor properties that we explored. The velocity range of the flat distribution for typical GRB parameters is γβ ≈ 0.03–3, where γ is the outflow Lorentz factor and β is its dimensionless velocity. A flat distribution is seen also for collimated choked jets where the highest outflow velocity decreases with the depth at which the jet is choked. Comparison to observations of SN/GRBs strongly disfavors jets as the sole explosion source in these events. Instead, in SN/GRB the collapsing star seems to deposit its energy into two channels – a quasi-spherical (or wide angle) channel and a narrowly collimated one. The former carries most of the energy and is responsible for the SN sub-relativistic ejecta while the latter carries 0.01–0.1 of the total outflow energy and is the source of the GRB. Intriguingly, the same two channels, with a similar energy ratio, were seen in the binary neutron star merger GW170817, suggesting that similar engines are at work in both phenomena.
Transcription-coupled donor DNA expression increases homologous recombination for efficient genome editing
Authors: Gao Kaixuan , Zhang Xuedi , Zhang Zhenwu , Wu Xiangyu , Guo Yan , Fu Pengchong , Sun Angyang , Peng Ju , Zheng Jie , Yu Pengfei , Wang Tengfei , Ye Qinying , Jiang Jingwei , Wang Haopeng , Lin Chao-Po , Gao Guanjun 
Published: August 2022

AbstractGenomes can be edited by homologous recombination stimulated by CRISPR/Cas9 [clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated peptide 9]-induced DNA double-strand breaks. However, this approach is inefficient for inserting or deleting long fragments in mammalian cells. Here, we describe a simple genome-editing method, termed transcription-coupled Cas9-mediated editing (TEd), that can achieve higher efficiencies than canonical Cas9-mediated editing (CEd) in deleting genomic fragments, inserting/replacing large DNA fragments and introducing point mutations into mammalian cell lines. We also found that the transcription on DNA templates is crucial for the promotion of homology-directed repair, and that tethering transcripts from TEd donors to targeted sites further improves editing efficiency. The superior efficiency of TEd for the insertion and deletion of long DNA fragments expands the applications of CRISPR for editing mammalian genomes.
BSCI-06 COMPREHENSIVE ANALYSIS OF THE IMMUNOGENOMICS OF TRIPLE NEGATIVE BREAST CANCER BRAIN METASTASES FROM LCCC1419
Authors: Van Swearingen Amanda , Routh Eric , Sambade Maria , Vensko Steven , McClure Marni , Woodcock Mark , Chai Shengjie , Cuaboy Luz , Wheless Amy , Garrett Amy , Carey Lisa , Hoyle Alan , Parker Joel , Vincent Benjamin , Anders Carey 
Published: August 2022

Abstract

BACKGROUND
Triple negative breast cancer (TNBC) lacks expression of hormone receptors (estrogen and progesterone receptors, ER and PR) and HER2. Almost 50% of patients with metastatic TNBC will develop brain metastases (BrM), often with concurrent progressive extracranial disease. While immunotherapy has shown promise in the treatment of advanced TNBC, the immune profile of BrM remains largely unknown. To inform the development of immunotherapy strategies in this aggressive disease, we characterized the genomic and immune landscape of TNBC BrM and matched primary tumors.

METHODS
Formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n=25, n=9 matched pairs) from the LCCC1419 biobank at UNC-Chapel Hill were analyzed by whole exome (WES) and RNA sequencing, with matched blood DNA sequenced for identification of somatic variants. Mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.

RESULTS
Primary and BrM tissues were confirmed as TNBC and of the basal intrinsic subtype. Compared to primary tumors, BrM demonstrated higher tumor mutational burden. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM, and predicted single nucleotide variants (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.

CONCLUSIONS
BrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Further research will expand these findings to other breast cancer subtypes. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM are warranted.
BSCI-10 TAPPING INTO GLIOMAS’ SECRETS: CSF PROTEOMICS FOR BIOMARKER DISCOVERY, GLIOMA MONITORING, AND THERAPEUTIC RESPONSE ASSESSMENT
Authors: Riviere-Cazaux Cecile , Ikram Samar , Chantigian Siobhan , Rahman Masum , Warrington Arthur , Burns Terry 
Published: August 2022

Abstract

INTRODUCTION
Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response.

METHODS
Global proteomic analysis of CSF was performed on the Somalogic platform − an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples.

RESULTS
Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden.

CONCLUSION
Our preliminary data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas.
BSCI-11 GB5121 IS A NOVEL, IRREVERSIBLE, COVALENT BTK INHIBITOR WITH HIGH SELECTIVITY AND CNS-PENETRANCE FOR TREATMENT OF CNS MALIGNANCIES
Authors: Yusuf Isharat , Guimond David , Naiman Zachary , Schiff Theodore , Clemons Bryan , Paulson Bryanna , Hou Kay , Meadows Kristen Taylor , Rose Mark , Carter Laura 
Published: August 2022

Abstract
Inhibitors of Bruton’s tyrosine kinase (BTK) are approved treatments for several B cell lymphomas. However, they are characterized by modest selectivity and/or limited central nervous system (CNS) exposure which is important in instances of CNS disease. GB5121 is an orally available, selective, irreversible, covalent small molecule BTK inhibitor that was designed to address these limitations. Here, GB5121 was profiled for selectivity, potency, inactivation kinetics and CNS penetrance in comparison to ibrutinib. GB5121 pharmacodynamic properties were evaluated using both cell-free enzymatic and cell-based functional assays, showing nM potency for BTK inhibition and rapid BTK inactivation kinetics (Kinact/Ki) in both peripheral and CNS tissue, a critical parameter for irreversible inhibitors. In a kinome scan, GB5121 exhibited high kinase selectivity against 349 kinases with only TEC/TXK demonstrating &gt;50% inhibition at 1 µM; GB5121 did not inhibit phosphorylation of EGFR in a cell-based assay. When compared with other BTK inhibitors, GB5121 showed superior CNS target occupancy using a probe-based ELISA measuring free BTK in the brain of mice receiving 3 daily oral doses. GB5121 also demonstrated significantly higher brain to plasma ratio in mice with an intact blood brain barrier. In non-human primates, a 1:1 brain to plasma concentration ratio was demonstrated for GB5121 for up to 8 hours with both oral (30 mg/kg) and IV (2 mg/kg) doses. Together, these features differentiate GB5121 from both FDA-approved BTK inhibitors, as well as those currently under clinical investigation. Our data supports the use of GB5121 in clinical trials where BTK is a known driver of malignancies, including CNS lymphoma. This research has been previously presented at the AACR Annual Meeting 2022.
BSCI-19 A LENTIVIRAL CRISPR SCREEN FOR EPIGENETIC MODULATORS OF ANTIGENS TARGETED BY CAR T CELLS IN GLIOBLASTOMA
Authors: Jordan Walter T , Jangde Nitish , Ayad Nagi 
Published: August 2022

Abstract
Glioblastoma (GBM) is the most common adult brain tumor and is very difficult to treat. One promising treatment strategy is CAR T cell therapy, in which T cells are used to target and kill cancer cells. However, CAR T cell therapy is not always effective, and more work is needed to realize its potential. One strategy for improving the efficacy of CAR T cell therapy is to increase the expression of targeted antigens on the surface of cancer cells. Our goal in these studies is to identify pathways that could be modulated to increase expression of the targeted antigens. Focusing on epigenetic proteins, we performed a lentiviral CRISPR screen in the human GBM cell line LN18. A lentiviral library was used to knock out various epigenetic genes in these cells in vitro. Following transduction, we use flow cytometry to examine surface expression of antigens currently being targeted in GBM clinical trials of CAR T cells, e.g. - GD2, B7-H3, etc. Cells with increased expression of the antigens of interest were selected using FACS. Genomic DNA was isolated from these cells and sequencing was performed to determine which epigenetic genes had been knocked out. Results showed multiple genes contributing to increased surface expression of targeted antigens. Future studies will determine whether small molecule inhibitors of the identified epigenetic pathways selectively induce up-regulation of these antigens in GBM cells in vivo.
CLRM-09 FIRST-LINE Tumor TREATING FIELDS (200 KHZ) THERAPY FOR NEWLY-DIAGNOSED GLIOBLASTOMA: THE PHASE 3 TRIDENT TRIAL (EF-32)
Authors: Shi Wenyin , Kleinberg Lawrence , Jeyapalan Suriya A , Goldlust Samuel A , Nagpal Seema , Roberge David , Nishikawa Ryo , Grossman Rachel , Glas Martin 
Published: August 2022

Abstract

BACKGROUND
Tumor Treating Fields therapy (TTFields; 200 kHz) comprise alternating electric fields that disrupt cancer cell division, and is approved for newly diagnosed glioblastoma (ndGBM), recurrent GBM and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. Additionally, TTFields added to RT/TMZ was reported as feasible and well-tolerated in 2 clinical pilot phase 2 studies.

MATERIALS AND METHODS
TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomized trial comparing TTFields (200 KHz, ≥18 h/day)/RT/TMZ vs RT/TMZ alone. Adult patients (N=950; ≥18 years of age [≥22 years of age; US]) with histologically confirmed ndGBM, Karnofsky Performance Status ≥70, life expectancy ≥3 months, adequate organ function and eligible for RT/TMZ will be enrolled. Patients will be stratified by extent-of-resection and MGMT promoter methylation status and randomized 1:1 to receive continuous TTFields/RT/TMZ or RT/TMZ during the investigational period. Subsequently, all patients will receive TTFields/6 cycles of maintenance TTFields/TMZ; TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO). The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs and quality-of-life, OS per TTFields duration-of-usage. The study is powered at 80% to detect a hazard ratio of &lt;0.8 (5% type I error). The study is currently open to enrolment in Austria, Belgium, Czech Republic, France, Germany, Israel, Switzerland, and across the US.
CLRM-12 TITLE: STEREOTACTIC RADIOSURGERY (ADJUVANT OR NEOADJUVANT) COMPARED TO HIPPOCAMPAL AVOIDANCE WHOLE BRAIN RADIATION THERAPY WITH SIMULTANEOUS INTEGRATED BOOST FOR LIMITED BRAIN METASTASES (SRS-CHART): PHASE III OPEN-LABEL PARALLEL-GROUP RANDOMIZED CONTROLLED TRIAL
Authors: Dasgupta Archya , Selvarajan Jeevi , Chatterjee Abhishek , Moiyadi Aliasgar , Shetty Prakash , Singh Vikas , Sahu Arpita , Bhattacharya Kajari , Sridhar Epari , Sahay Ayushi , Shah Aekta , Joshi Kishore , Kinhikar Rajesh , Kannan Sadhana , Gupta Tejpal 
Published: August 2022

Abstract

BACKGROUND
Surgery is indicated for large or symptomatic lesions in patients with limited brain metastasis (BM), followed by adjuvant stereotactic radiosurgery (A-SRS) to the cavity. Emerging evidence suggests promising role of neoadjuvant SRS (NA-SRS) before surgery with potentially lesser risk of leptomeningeal disease (LMD) and radionecrosis (RN). Hippocampal avoidance whole brain radiotherapy (HA-WBRT) results in better neurocognitive outcomes than standard WBRT, and use of simultaneous integrated boost (SIB) to surgical cavity can improve the local control. Absence of high-quality evidence forms the basis of current study comparing these three treatment strategies.

OBJECTIVES
Primary endpoint is 1-year event-free survival (EFS) a composite endpoint comprising any local failure, LMD, DBF, symptomatic RN, or death as events. Other endpoints include individual endpoints and longitudinal neuro-cognitive function and quality-of-life assessment.

METHODS
Target population includes adults with newly diagnosed BM (≤3 lesions) with life expectancy &gt;1 year and one target lesion needing surgery. Patients will be randomized (1:1:1) to A-SRS (control arm) or one of two test arms (NA-SRS or HA-WBRT-SIB). In A-SRS arm, patients will receive single fraction (16-20Gy) or hypofractionated-SRS (24-27Gy/3 fractions or 30-32.5Gy/5 fractions) based on volume and location of cavity and other intact BM. In the test arms, patients will be allocated to either NA-SRS group (single/multi-fraction) followed by surgery within 2 weeks or HA-WBRT (30Gy/10 fractions) with SIB to cavity plus other intact BM (40-50Gy/10 fractions) combined with memantine within 6 weeks of surgery. A sample size of 168 patients is required to prove the superiority of test arms individually compared to the control arm with assumption of 1-year EFS of 43% versus 25% with a hazard ratio of 0.6 (two-sided alpha=0.05, power=80%, and 15% attrition rate).

DISCUSSION
The study will generate level 1 evidence investigating the role of NA-SRS or HA-WBRT-SIB compared to A-SRS in limited brain metastases.
CLRM-21 RISK FACTORS ASSOCIATED WITH THE PRESENCE OF BRAIN METASTASIS AT THE MOMENT OF DIAGNOSIS IN LUNG CANCER PATIENTS: RETROSPECTIVE CASE SERIES
Authors: Martín-Abreu Carla M , Fariña-Jerónimo Helga , Plata-Bello Julio 
Published: August 2022

Abstract

BACKGROUND
Lung cancer (LC) is the second most frequent neoplasm worldwide and it is commonest origin of brain metastases (BM). The aim of this study is to identify clinical, histological and molecular variables associated with a higher risk of BM at diagnosis in LC patients.

METHODS
A retrospective single-centre case series analysis of patients with a new diagnosis of LC (from 2015 to 2018) was performed. A total of 723 newly diagnosed LC patients were identified and only those with a brain imaging study were included. Non-parametric statistical tests were used to compare patients with or without metastases at diagnosis. Uni- and multivariate analysis was performed to identify risk factors associated with the presence of BM. Statistical significance was considered when p&lt;0.05.

RESULTS
185 patients with newly diagnosed LC and brain imaging at diagnosis were included (mean age 64.69 years [SD= 10.34]; 71.9% male). 40% of patients had BM at diagnosis. No significant differences in clinical, histological and molecular variables were identified. In any case, survival analysis showed that BM at diagnosis was associated with worse overall survival (Log-Rank test, p&lt;0.01). Univariate analysis showed that presenting neurological symptoms (OR=19.5, p&lt;0.0001 CI [7.895-47.65]), adenocarcinoma (OR= 2.113, p&lt;0.014 CI [1.160-3.849]), small cell carcinoma (OR=0.372, p&lt;0.008 CI [0. 179-0.773]) and visceral metastases (OR= 14.444, p&lt;0.0001 CI [6.161-33.86]) or metastases limited to the thorax (OR= 0.019, p&lt;0.001 CI [0.003-0.146]) were associated with BM at diagnosis. However, only neurological symptoms (OR= 20.290, p&lt;0.0001 CI [4.953-83.118]), visceral metastases (OR= 4.451, p&lt;0.010 CI [1.458-13.777]) and/or metastases limited to the thorax (OR= 0.066, p&lt;0.024 CI [0.006-0.010]) reached statistical significance in multivariate analysis.

CONCLUSIONS
Neurological symptoms and the presence of visceral metastases are independent predictors of developing BM at diagnosis in LC patients. However, LC disease confined to the thorax is associated with a lower risk of developing BM.
SPIN-01 RADIATION THERAPY ALONE VERSUS RADIATION THERAPY PLUS RADIOFREQUENCY ABLATION/VERTEBRAL AUGMENTATION FOR SPINE METASTASIS: TRIAL IN PROGRESS
Authors: Kotecha Rupesh , Schiro Brian , Sporrer Justin , Rubens Muni , Avendano Maria , Appel Haley , Tom Martin , Mehta Minesh 
Published: August 2022

Abstract

BACKGROUND
Spine metastases are a common occurrence in cancer patients and result in pain, neurologic deficits, decline in performance status, disability, inferior quality of life (QOL), and reduction in ability to receive cancer-directed therapies. Conventional external beam radiation therapy (EBRT) is associated with modest rates of pain relief, high rates of disease recurrence, low response rates for those with radioresistant histologies, and limited improvement in neurologic deficits. The addition of radiofrequency ablation/percutaneous vertebral augmentation (RFA/PVA) to index sites together with EBRT may improve pain response rates and corresponding quality of life.

METHODS/DESIGN
This is a single-center, prospective, randomized, controlled trial in patients with spine metastases from T5-L5, stratified according to tumor type (radioresistant vs. radiosensitive) in which patients in each stratum are randomized in a 2:1 ratio to either RFA/PVA and EBRT or EBRT alone. All patients are treated with EBRT to a dose of 20-30 Gy in 5-10 fractions. The target parameters are measured and recorded at the baseline clinic visit, and daily at home with collection of weekly measurements at 1, 2, and 3 weeks after treatment, and at 3, 6, 12, and 24 months following treatment with imaging and QOL assessments.

DISCUSSION
The primary objective of this randomized trial is to determine whether RFA/PVA in addition to EBRT improves pain control compared to palliative EBRT alone for patients with spine metastases, defined as complete or partial pain relief (measured using the Numerical Rating Pain Scale [NRPS]) at 3 months. Secondary objectives include determining whether combined modality treatment improves the rapidity of pain response, duration of pain response, patient reported pain impact, health utility, and overall QOL. The results from this study will be used to allow for comparisons to alternative treatment approaches. This trial was activated 5/2020 and is open to accrual.