bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone microstructure changes due to once-/twice-weekly teriparatide administration: A report of five cases using high-resolution peripheral quantitative computed tomography
Authors: Tsukamoto Manabu , Okimoto Nobukazu , Mori Miyuki , Yoshioka Toru , Asano Kei , Ikejiri Yoshiaki , Uzawa Toyonobu , Yoshimura Takeshi , Suzuki Hiroaki , Yamanaka Yoshiaki , Kawasaki Makoto , Sakai Akinori 
Published: November 2021

ABSTRACT
This study was conducted with the aim of presenting cases in which high-resolution peripheral quantitative computed tomography (HR-pQCT) was used to investigate changes in the bone microstructure due to once-weekly/twice-weekly administration of teriparatide (TPTD). Of osteoporosis patients who participated in a non-inferiority trial (TWICE study: once-weekly vs twice-weekly TPTD) with lumbar bone mineral density as the primary endpoint, five cases scanned by HR-pQCT before TPTD administration were analysed. Two cases were given once-weekly TPTD, three were given twice-weekly TPD, and HR-pQCT was repeated after 48 weeks. A sufficient anabolic effect of once-weekly/twice-weekly TPTD on the trabecular and cortical bone at the tibia was obtained. In addition, the average change in cortical porosity (Ct.Po) was only 0.3% in the tibia and 0.2% in the radius. These findings indicate that once-weekly and twice-weekly TPTD can be expected to improve the bone microstructure, and the increase in Ct.Po may be suppressed.
The Effect of Music Therapy on Perceived Parental Stress in Perinatal Care: An Exploratory Study
Authors: Bollard-Marcovitz Jenna , Tachdjian Raffi , Roa Esteban , Flores Luisa , Brown Scott , Gill Amira , Brown Chelsea , Wicks Eiress , Danelyan Hranush , Tan Mint , Pak Grace , Pincus Bethany , Petrey-Juarez Julia 
Published: November 2021

Abstract
The perinatal experience contains many stressors that can impact parental mental health. We examined the integration of music therapy (MT), an evidence-based health profession, and its stress reduction role in parents during their inpatient maternity and neonatal intensive care unit (NICU) experience. The Perceived Stress Scale (PSS) and Stress Numeric Rating Scale (SNRS-11) were used to measure stress reduction in 34 maternity and NICU parents (17 maternity patients and 17 NICU parents). Participants included parents on the antepartum unit (expecting parents on bedrest), laboring parents, pre-operation parents before cesarean delivery, parents of full-term healthy infants on the postpartum unit, and parents of premature infants on the NICU. Results were calculated based upon number of sessions rather than total number of participants and indicated that after one MT session, a 50% reduction in the SNRS-11 was measured in NICU and antepartum parents. The PSS score demonstrated a more modest stress reduction in the NICU parents but failed to achieve a statistically significant decrease in the maternity group. Findings were in line with existing literature in MT-associated stress reduction levels and may be integrated as part of an ongoing continuity of care during pregnancy, delivery, and NICU hospitalization. Earlier screening for stress may benefit parents during their perinatal hospital stay. Further research exploring the benefits of MT, as part of continuum of care and stress management for the inpatient perinatal parent population, may encourage the inclusion of MT services and improve quality of care.
EPCO-03. GLIOMA ONCOGENESIS IN THE CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD) SYNDROME
Authors: Guerrini-Rousseau Léa , Merlevede Jane , Denizeau Philippe , Andreiuolo Felipe , Varlet Pascale , Puget Stéphanie , Beccaria Kevin , Blauwblomme Thomas , Cabaret Odile , Hamzaoui Nadim , Bourdeaut Franck , Faure-Conter Cécile , Muleris Martine , Colas Chrystelle , de Beaumais Tiphaine Adam , Castel David , Rouleau Etienne , Brugières Laurence , Grill Jacques , Debily Marie-Anne 
Published: November 2021

Abstract

PURPOSE
Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context.

METHODS
A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas).

RESULTS
Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden.

CONCLUSION
CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
EPCO-08. ATRX DEFICIENCY INDUCES DYSFUNCTIONAL HETEROCHROMATIN ARCHITECTURE IN GLIOMAS AND ESTABLISHES DISEASE-DEFINING TRANSCRIPTIONAL NETWORKS
Authors: Malgulwar Prit Benny , Danussi Carla , Singh Anand , Kannan Kasthuri , Rai Kunal , Huse Jason 
Published: November 2021

Abstract
Loss of ATRX (Alpha Thalassemia/Mental Retardation Syndrome X, a member of SWI/SNF family chromatin regulator is altered in diffuse gliomas and defines molecular subtypes with aggressive behavior. Mechanistically, ATRX regulates incorporation of histone H3.3 into chromatin sites across the genome, maintains alternative lengthening of telomeres and establishes genomic distribution of polycomb responsive genes. We have recently reported Atrx deficiency induces glioma oncogenic features via widespread alterations in chromatin accessibility using mouse Neural Progenitor Cells (mNPCs- Tp53 -/-,Atrx -/-). Surprisingly, Atrx was found to be associated with transcription start site and enhancer regions, suggesting their strong association with epigenome architecture. In this background, we have recently performed ChIP-seq for histone marks that define active transcription, enhancers, repressors and gene bodies and Cohesion molecules on Atrx intact and deficient mNPCs. Our integrated analysis reports depletion of H3K9me3 loci’s with enrichment of H3K27me3 marks that coincidently enriched with Atrx binding sites and Lamina-Associated Domains (LADs). GSEA confirmed that the genes corresponding to “newly formed LADs” in mNPC-to-astrocyte differentiation are significantly enriched for genes down-regulated in Atrx deficient mNPCs and belongs to Gene Ontology categories such as cell cycle, chromosome organization and DNA damage. Alternatively, genes corresponding to decreased LAD association are enriched for up-regulated genes in Atrx deficient mNPCs and for regulation of differentiation, adhesion and cell death. Additionally, whole-genome bisulphite sequencing further demonstrated loss of methylation marks at H3K9me3 sites in Atrx deficient mNPCs, suggesting perturbations of heterochromatin regions leading to activation of canonical signals that define glioma phenotype and disease-state. To summarize, our data establishes tangible links between Atrx deficiency and dysregulated chromatin and heterochromatin architecture in gliomas and suggests the role of Atrx in establishing global chromatin features and transcriptional networks. Further, our data unravel novel therapeutic molecules/pathways for engineering potential.
EPCO-11. SINGLE-NUCLEI TRANSCRIPTOMICS RELATES GLIOBLASTOMA INFILTRATION TO DISTINCT GLIAL PROGENITOR STATES
Authors: Mussa Zarmeen , Ramos Susana , Beaumont Kristin , Sebra Robert , Tsankov Alexander , Tsankova Nadejda 
Published: November 2021

Abstract
Our understanding of glioblastoma (GBM) intratumoral heterogeneity, particularly in the context of neurodevelopment, has thus far been primarily focused on the more surgically accessible tumor core niche. In contrast, the biology of GBM cells at the infiltrative edge, which evade surgical resection and drive tumor recurrence, remains poorly characterized. To this end, we microdissected and performed single-nuclei RNA sequencing (snRNA-seq) on approximately 62,000 nuclei taken from the tumor core and from the infiltrative edge of six GBM tumors with diverse genomic drivers, including IDH1, EGFR, PDGFRA, FGFR3, and NF1. Unbiased clustering reveals distinct neoplastic and non-neoplastic populations, further distinguished using copy number variation analysis. After projecting previously defined signatures taken from snRNA-seq analysis of human adult neocortex/subventricular zone and prenatal germinal matrix, we find that approximately 90% of tumor cells recapitulate a neurodevelopment-like molecular phenotype, reprising gene expression signatures of prenatal astrocytes and of a distinct glial intermediate progenitor cell population (g-IPC) that precedes both astrocyte and oligodendrocyte lineage differentiation. Examining the infiltrative edge of samples with the most confident microdissection (n=4), we see that while distinct populations of tumor cells in this niche express proneural and classical signatures, these cells are overall enriched for a g-IPC-like phenotype, relative to the tumor core, irrespective of the tumors’ genomic alterations. A subset of cells at the infiltrative edge, in particular, recapitulates the signature of an uncommitted g-IPC subtype, expressing both astroglial and oligodendroglial markers. Trajectory analyses also reveal distinct branches of core and edge tumor cells, which are predominantly astrocyte- and g-IPC-like, respectively. Differential gene expression analysis of GBM cells at the infiltrative edge vs. tumor core reveals a migration signature, dominated by EGFR, ERBB4, PCDH9, and PCDH15. Ultimately, this high resolution analysis of heterogeneity at the infiltrative edge allows us to uncover potentially targetable drivers of invasion in GBM.
EPCO-18. A MESENCHYMAL CELL POPULATION MEDIATES RESISTANCE TO AURORA KINASE INHIBITORS IN GLIOBLASTOMA
Authors: Suter Robert , Stathias Vasileios , Jermakowicz Anna , Pradhyumnan Hari , Affer Maurizio , Guglielmetti Florence , Ivan Michael , Komotar Ricardo , de la Fuente Macarena , Sarkaria Jann , Schürer Stephan , Ayad Nagi 
Published: November 2021

Abstract
Glioblastoma (GBM) remains the most common adult brain cancer, with a dismal average patient survival of less than two years. No new treatments have been approved for GBM since the introduction of the alkylating agent temozolomide in 2005. Even then, temozolomide treatment only increases the average survival of GBM patients by a few months. Thus, novel therapeutic options are direly needed. The aurora kinases A and B are targetable and overexpressed in GBM, and their expression is highly correlated with patient survival outcomes. Our lab has found that small molecule aurora kinase inhibition reduces GBM tumor growth in vitro and in vivo, however, eventually tumors still grow. Computational analysis integrating compound transcriptional response signatures from the LINCS L1000 dataset with the single-cell RNA-sequencing data of patient GBM tumors resected at the University of Miami predicts that aurora inhibition targets a subset of cells present within any GBM tumor. Results of in vivo single-cell perturbation experiments with the aurora kinase inhibitor alisertib coincide with our predictions and reveal a cellular transcriptional phenotype resistant to aurora kinase inhibition, characterized by a mesenchymal expression program. We find that small molecules that are predicted to target different cell populations from alisertib, including this resistant mesenchymal population, synergize with alisertib to kill GBM cells. As a whole, we have identified the cellular population resistant to aurora kinase inhibition and have developed an analytical framework that identifies synergistic small molecule combinations by identifying compounds that target transcriptionally distinct cellular populations within GBM tumors.
EPCO-21. CORE REGULATORY CIRCUIT TRANSCRIPTION FACTORS DRIVE EXPRESSION FROM HIGH LEVEL AMPLICONS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Deng Davy , Dubois Frank , Crane Alexander , Harutyunyan Ashot , Beroukhim Rameen , Bandopadhayay Pratiti 
Published: November 2021

Abstract

BACKGROUND
Pediatric High-Grade Gliomas (pHGGs) show recurrent high-level amplifications around the oncogenes MET, MYCN and EGFR. However what drives expression of the oncogenes from these amplicons remains unclear. We aim to discover enhancers on these amplicons that are responsible for oncogene expressions and the core regulatory transcription factors (TFs) they bind.

METHOD
Using RNA-seq from 12 pHGG cell lines, we identified groups of high and low-expressing pHGG lines for MET, MYCN and EGFR. We then compared the H3K27Ac ChIP-seq between the two groups using diffbind. This allowed us to identify statistically significant peaks that are differentially activated in the oncogene-high v.s. oncogene-low expressing groups. Additionally, we overlapped the positions of these candidate oncogene enhancers with the regions that are recurrently incorporated into high-level amplicons based on published whole genome sequencing data. Using a previously defined set of core regulatory TFs we determined which TF binds the amplified oncogene enhancers and could be driving oncogenic expressions of MET, MYCN and EGFR in pHGGs.

RESULTS
We identify 3 cell lines for both the high- and low-expressing groups for each oncogene. Cell lines with high expression of the oncogene showed distinct enhancers with significant enrichment in H3K27Ac compared to the cell lines with low expression for each oncogene. Of all enhancers with enrichment high oncogene expression groups those with binding sites for known pHGG core regulatory circuit TF were preferentially incorporated into the high-level amplicons of the oncogene. We also identified core TFs that bind enhancers for MYCN, EGFR and MET as well as core TFs that are unique to a single oncogene.

CONCLUSION
We identified candidate core transcription factor that drives expression of multiple oncogenes in pHGG. These could serve as a potential novel therapeutic target for pHGGs with addiction to MYCN or RTK signaling.
EPCO-24. MACHINE LEARNING ALGORITHMS UTILIZING TRANSCRIPTIONAL SIGNATURES PREDICT SURVIVAL OUTCOMES IN GLIOMA
Authors: Zhou zhaoming , Lai Mingyao , Li Juan , Hu Qingjun , Shan Changguo , Zhou Cheng , Cai Linbo 
Published: November 2021

Abstract

BACKGROUND
Glioblastomas (GBM) is a common primary malignant brain tumor. This study performed RNA-seq with 227 glioma samples with the aim to identify the immune-related gene markers for glioma prognosis prediction.

METHODS
Differentially expressed genes (DEGs) were identified between glioma and healthy samples in the TCGA dataset. Differentially expressed immune-related genes (DE-IRGs) were determined by intersecting DEGs to the immune-related genes in the ImmProt database. Independent survival associated DE-IRGs were selected by univariate and multivariate cox-regression analysis in TCGA dataset and validated in the CGGA databases and our RNA-seq data. Further enrichment analysis demonstrated the hub-genes among those prognosis-associated DE-IRGs. After the expression of hub-genes were confirmed by immunohistochemistry (IHC), the hub-genes protein levels on slides were further utilized to establishing the prognosis prediction models by several machine learning methods, including least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM) and linear discriminant analysis (LDA).

RESULTS
There were 404 DE-IRGs determined in glioma in comparison with healthy tissue samples in TCGA. After evaluated by univariate and multivariate cox-regression, 55 DE-IRGs remaining significant. Thirty-four DE-IRGs were verified to be survival associated in both CGGA and our sequencing cohort, among which, 4 hub-genes (LIF and MDK, LAMB1, and CALU) were determined by enrichment analysis. All of the 4 hub-genes were expression confirmed on the protein level by IHC staining. Based on the staining results, a survival risk score (SRS) was established by machine learning methods (GLM, LDA, and LASSO). Based on SRS, glioma patients were divided into high- and low-risk groups, the overall survivals were significantly different between those two groups, regardless of the tumor grades or pathology types.

CONCLUSIONS
This study identified a potential immune prognostic signature (LIF and MDK, LAMB1, and CALU) of glioma that would be helpful for OS predicting and for potential therapeutics development.
EPCO-25. MULTI-OMICS DISEASE STRATIFICATION IN PATIENTS WITH IDH-WILDTYPE GLIOBLASTOMA: SYNERGISTIC VALUE OF CLINICAL MEASURES, CONVENTIONAL AND DEEP RADIOMICS, AND GENOMICS FOR PREDICTION OF OVERALL SURVIVAL
Authors: Kazerooni Anahita Fathi , Saxena Sanjay , Tu Danni , Toorens Erik , Bashyam Vishnu , Akbari Hamed , Mamourian Elizabeth , Sako Chiharu , Koumenis Costas , Shinohara Russell T , Bagley Stephen J , Desai Arati , Lustig Robert A , O’Rourke Donald M , Ganguly Tapan , Bakas Spyridon , Nasrallah MacLean , Davatzikos Christos 
Published: November 2021

Abstract

PURPOSE
Multi-omics data integration captures tumor characteristics at multiple scales [i.e., microscopic (genomics and epigenetics), macroscopic (radiomics), clinical manifestation], provides a more comprehensive assessment of patient’s risk, and facilitates personalized therapies. In this work, we investigated the synergistic value of such multiple data sources for risk stratification and prediction of overall survival in IDH-wildtype glioblastoma tumors.

METHODS
Quantitative conventional and deep radiomics were extracted from pre-operative multi-parametric structural MRI (T1, T1Gd, T2, T2-FLAIR) of 501 patients with newly diagnosed glioblastoma. 389/501 and 112/501 patients formed our discovery and replication cohorts, respectively. Conventional radiomics were extracted from CaPTk, and deep radiomics from a pre-trained VGG-19 model. Multivariate SVM classification was performed on the discovery cohort to stratify patients in high, medium, and low-risk groups, using recursive feature elimination and 5-fold cross-validation. This model was independently tested on the replication cohort, and a radiomic-based survival prediction index (SPIradiomics) was calculated for each patient. Multi-stage integration of omics data, i.e., clinical (age, gender, extent of resection (EOR)), SPIradiomics, epigenetics (MGMT promoter methylation), and genomics (27 clinically relevant gene mutations via next-generation sequencing (NGS)), was performed using multivariate Cox proportional hazards (Cox-PH) model for stratification of the risk in the replication cohort.

RESULTS
Cox-PH modeling resulted in a concordance index (c-index) of 0.65 (95% CI:0.6–0.7) for clinical data, 0.67 (95% CI:0.62–0.72) for clinical and epigenetics, 0.70 (95% CI:0.65–0.75) for clinical and radiomics, 0.72 (95% CI:0.68–0.77) for clinical, epigenetics, and radiomics, and 0.75 (95% CI:0.71 – 0.78) for the multi-omics combination of all data; highlighting the added value of each layer of information in prediction of the patient’s risk.

CONCLUSION
Our results reinforce the synergistic value of integrated diagnostic methods for improving risk assessment of patients with glioblastoma that may pave the path towards a more personalized treatment planning.
BIOM-04. SENSITIVE DETECTION OF LEPTOMENINGEAL DISEASE USING CELL-FREE DNA FROM CEREBROSPINAL FLUID
Authors: White Michael , Klein Robert , Shaw Brian , Kim Albert , Subramanian Megha , Mora Joana , Giobbie-Hurder Anita , Nagabhushan Deepika , Jain Aarushi , Singh Mohini , Kuter Benjamin , Nayyar Naema , Stocking Jackson , Markson Samuel , Lastrapes Matthew , Alvarez-Breckenridge Christopher , Cahill Daniel , Mahar Maura , Rhoades Justin , Rotam Denisse , Bertalan Mia , Gydush Greg , Adalsteinsson Viktor , Kaplan Alexander , Oh Kevin , Sullivan Ryan , Gerstner Elizabeth , Carter Scott , Brastianos Priscilla 
Published: November 2021

Abstract
Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.