bluuebunny/crossref_metadata_2025_split huggingface dataset:
CBIO-20. MOLECULAR MECHANISMS OF OLIG2 TRANSCRIPTION FACTOR IN GLIOBLASTOMA
Authors: Saito Norihiko , Sato Sho , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Ito Keisuke , Sakurai Takatoshi , Iwabuchi Satoshi 
Published: December 2020

Abstract
Oligodendrocyte lineage transcription factor 2 (OLIG2) promotes proliferation of normal neural stem/progenitor cells and glioma cells. However, the mechanisms underlying the regulation of OLIG2 remain largely unknown. Here, we show that a comprehensive analysis of the critical gene regulatory networks involving OLIG2 in glioma initiating cell (GIC) lines. In vitro differentiation studies showed that proneural GIC lines possess the potential to differentiate into astrocytic, neuronal, and oligodendrocytic lineages, whereas mesenchymal GICs exhibited limited potential for neural lineage differentiation following retinoic acid induction. We also showed that CDK2-mediated OLIG2 phosphorylation stabilizes OLIG2 protein from proteasomal degradation. Phosphorylated OLIG2 binds to the E-Box regions of p27 promoter and represses p27 transcription, which in turn activates CDK2 in positive feedback manner. CDK2-mediated OLIG2 phosphorylation promotes cell cycle progression, cell proliferation, and tumorigenesis. OLIG2 inhibition disrupted cell cycle control mechanism by decreasing CDK2 and elevating apoptosis-related molecules. Inhibition of CDK2 activity disrupted OLIG2-CDK2 interactions and attenuated OLIG2 protein stability.　In addition, OLIG2-high glioma initiating cells are highly sensitive to CDK2 inhibitor treatment, indicating that OLIG2 can be a biomarker for personalized treatment for glioblastoma patients with CDK2 inhibitors. In conclusion, we have identified OLIG2-CDK2 interactions in glioma stem cells that can be targeted by CDK2 inhibitors and this may allow the selection of patients with high likelihood of responding to this therapy.
CBIO-21. H3F3A G34R/V MUTATIONS INDUCE CHROMOSOMAL INSTABILITY AND PROMOTE PEDIATRIC HIGH-GRADE GLIOMA FORMATION
Authors: Day Charles , Grigore Florina , Langfald Alyssa , Robinson James , Hinchcliffe Edward 
Published: December 2020

Abstract
Histone H3.3 G34R/V mutations are drivers of pediatric high-grade glioma (pHGG). However, the mechanism(s) responsible for G34R/V induced tumorigenesis are unclear. We observed that pHGG cells with H3.3 G34 mutations have significantly reduced phosphorylation at H3.3 S31 as compared to H3.3 WT cell lines. And, in vitro, G34 mutation completely blocks H3.3 S31 phosphorylation by Chk1 – the kinase responsible for S31 phosphorylation. During early mitosis, phospho-S31 is enriched in the chromosomal pericentromere; which plays a vital structural role in chromosome segregation. Over-expression of GFP-H3.3 G34R or non-phosphorylatable GFP-H3.3 S31A in chromosomally stable cell lines results in a significant increase in chromosome mis-segregations. Likewise, H3.3 G34V pHGG derived cells showed a higher frequency of mis-segregation than H3.3 WT cells. During cell division, phospho-S31 is lost in late anaphase. However, when chromosome missegregation occurs, phospho-S31 spreads to the chromosome arms where it stimulates p53 accumulation in G1 – thus acting as a sensor to suppress the proliferation of aneuploid cells. Here we show that cells expressing mutant G34 fail to arrest following mis-segregation, despite having WT p53. Taken together this work demonstrates that the H3.3 G34R/V mutations are sufficient to transform normal, diploid cells into proliferative, chromosomally instable cells. To determine if this process contributes to tumorigenesis, we expressed WT H3.3, H3.3-G34R or H3.3-S31A in a mouse model of pHGG. H3.3 WT controls developed low-grade tumors and all survived 80 days. Mice with H3.3-G34R or H3.3-S31A developed low- and high-grade tumors. And 78% and 50% of H3.3-G34R and H3.3-S31A mice, respectively, survived to 80 days. Our work suggests that H3.3 G34R/V drives chromosomal instability through the suppression of H3.3 S31 phosphorylation AND that chromosomal instability is a contributing driver of glioma formation in G34 mutant tumors.
CBIO-22. p53 GAIN-OF-FUNCTION MUTATIONS DRIVE SEX SPECIFIC EFFECTS ON GLIOMA TUMORIGENESIS
Authors: Rockwell Nathan , Warrington Nicole , Rubin Joshua 
Published: December 2020

Abstract
Sex differences in malignant brain tumors are well-established: Males exhibit greater incidence and poorer survival. Understanding the biology behind these sex differences requires investigation of the pathways known to drive gliomagenesis. The transcription factor TP53 (p53) is one of the most commonly mutated genes in glioblastoma. Most p53 mutations are missense mutations in the DNA-binding domain that lead to the expression of a full length mutant p53 protein. These mutations can endow p53 with oncogenic gains-of-function through aberrant DNA binding and regulation of noncanonical cancer-promoting target genes. Previously, we analyzed patient mutation data and identified six p53 mutations with sex differences in prevalence. In this study, we developed an in vitro mutant p53 glioma model to investigate the sex specific effects of three p53 point mutations: R175H, Y205C, and Y220C (Mm R172H, Y202C, and Y217C respectively). Male and female astrocytes isolated from p53flox/- mouse pups were transduced with a retrovirus expressing mutant p53, followed by a lentivirus expressing CRE recombinase to remove the endogenous WTp53. We then assessed cell proliferation, clonogenicity, and in vivo tumorigenesis in these cells. All three mutations assayed displayed sex differences in proliferation, with male cells overexpressing p53:Y202C and p53:Y217C growing faster than female cells, and female cells overexpressing p53:R172H growing faster than male cells. Male Y202C and Y217C expressing astrocytes also exhibited a trend toward greater clonogenicity compared to female astrocytes. This observation is supported by higher expression of the stem cell markers SOX2 and NESTIN in the male cells. We performed parallel flank injections of male and female astrocytes expressing each mutation or p53 KO. Only male astrocytes expressing p53:Y202C or p53:Y217C and female astrocytes expressing p53:R172H mutation were able to form tumors in vivo. Together, these data support a sex specific gain-of-function phenotype for three different p53 mutations observed in glioma.
CBIO-23. PROXIMITY-DEPENDENT BIOTIN IDENTIFICATION (BIOID2) INDICATES MEMBRANE TRAFFICKING AND VESICLE TRANSPORT AS A POTENTIAL NOVEL FUNCTION OF EXTRACELLULAR SIGNAL-REGULATED KINASE 5 (ERK5)
Authors: Stanton Ann-Catherine , Koller Antonius , Koncar Robert , Golbourn Brian , Halligan Katharine , Halbert Matthew , Mack Stephen , Pollack Ian , Agnihotri Sameer 
Published: December 2020

Abstract

INTRODUCTION
Pediatric High-Grade Gliomas (PHGG), which include Diffuse Midline Gliomas (DMG), are a leading cause of brain tumor death in children. Our recent work has identified extracellular signal-regulated kinase 5 (ERK5) as a critical mediator of cell survival in DMG, as ERK5 knockdown decreases cell proliferation and extends survival time in orthotopic xenograft mice. Further investigation into the structure of ERK5 shows that it has a kinase domain and, unlike other ERKs, a transactivation domain, and both are important for promoting cell proliferation.

HYPOTHESIS AND METHODS
We hypothesize that identifying interactors and substrates of ERK5 could identify clinically actionable proteins and provide a more mechanistic insight into ERK5 in the progression of PHGGS. To determine protein–protein associations (PPAs), we employed the proximity-dependent biotin identification (BioID2) method and generated inducible ERK5-BioID2 and ERK2-BioID2 constructs to overcome barriers of conventional screening methods for PPAs. ERK2, similar in structure but much more studied than ERK5, was used as a comparison. Using DIPG lines as proof of principle, we performed streptavidin pull down assays for putative biotinylated ERK PPA and followed with mass spectrometry to identify the ERK2 and ERK5 interactomes.

RESULTS
Using data-dependent acquisition (DDA), we identified several unique and common interactors of ERK5 compared to ERK2. Through STRING network and pathway analysis, we identified a novel function of ERK5 with respect to membrane trafficking and vesicle transport. Identification of interactors with ERK5 may lead to effective therapeutic combinations. Our current work is focused on validating these interactions and the function of ERK5 in these biological processes.

CONCLUSIONS
Currently, ERK5 is not as understood as ERK1 or ERK2. Identification of interactors and substrates of ERK5 will further our understanding of PHGG biology, and may lead to identifying druggable targets and pathways.
COVD-01. ADAPTATION OF A GAMMA KNIFE ICON STEREOTACTIC RADIOSURGERY PROGRAM IN THE FACE OF A GLOBAL PANDEMIC
Authors: Wegner Rodney , Horne Zachary , Xu Linda , Yu Alexander , Goss Matthew , Liang Yun , Sohn Jason , Colonias Athanasios , Fuhrer Russell , Karlovits Stephen 
Published: December 2020

Abstract

PURPOSE
The COVID-19 pandemic necessitated drastic and rapid changes throughout the field of radiation oncology, some of which were unique to the discipline of radiosurgery. Available guidelines called for reduced frame use, postponing non-urgent cases, and reducing the number of fractions delivered. Our institution enacted many of these guidelines, and herein we show the resultant effect on patient treatments on our Gamma Knife Icon system.

METHODS & MATERIALS
In early to mid-March of 2020 our institution rapidly implemented suggested changes according to ASTRO and other consensus guidelines as they relate specifically to stereotactic radiosurgery in the COVID-19 era. We reviewed the GK Icon schedule at our institution between January 01 and April 30, 2020. We documented age, condition treated, technique (frame vs. mask), and number of fractions. We then tabulated and graphed the number of patients, framed cases, and fractions across that time period.

RESULTS
Seventy-seven patients were treated on the GK Icon between January and April 2020, for a total of 231 fractions. The number of unique patients per month varied from 18 (April) to 22 (January). Of the 77 patients only 5 were treated using a frame. The number of fractions per month decreased significantly over time, from 70 in January to 36 in April. Likewise, the percentage of single fraction cases increased from 4.5% per month in January to 67% in April.

CONCLUSIONS
The results presented here show that it is possible to quickly and efficiently change work flows to allow for reduced fractionation and frame use in the time of a global pandemic. Multidisciplinary cooperation and ongoing communication are integral to the success of such programs.
COVD-06. BRAIN TUMOURS AND COVID-19: THE PATIENT AND CAREGIVER EXPERIENCE
Authors: Voisin Mathew , Oliver Kathy , Farrimond Stu , Chee Tess ,   IBTA Senior Advisors, Zadeh Gelareh 
Published: December 2020

Abstract

BACKGROUND
Since the COVID-19 pandemic, thousands of medical procedures and appointments have been cancelled or delayed. The long-term effects of these drastic measures directly on brain tumour patients and their caregivers are unknown. The purpose of this study is to better understand how COVID-19 has affected this vulnerable population on a global scale.

METHODS
An online 79-question survey was developed by the IBTA, in conjunction with the SNO COVID-19 Task Force. The survey was sent to over 120 brain tumour charities and not-for-profits worldwide and disseminated to brain tumour patients and caregivers. All responses were subdivided by patient vs caregiver and by geographical region.

RESULTS
In total, 1989 participants completed the survey from 33 countries, including 1459 patients and 530 caregivers. There were no significant differences in COVID-19 testing rates (p = 0.662) or the number of positive cases for brain tumour patients between regions (p = 0.1068). Caregivers were significantly more anxious than patients (p = &lt; 0.0001). Patients from the Americas were most likely to have lost their jobs due to the pandemic, practiced self-isolation, and received telehealth services (p = &lt; 0.0001). Patients from Europe experienced the most treatment delays (p = 0.0031). Healthcare providers were ranked as the most trusted source of information.

CONCLUSIONS
As a result of COVID-19, brain tumour patients and caregivers have experienced significant stress and anxiety. Healthcare professionals, brain tumour charities, and not-for-profits must ensure that they continue to provide accessible, high-quality care, information, and support in the age of COVID-19.
COVD-13. EFFECTS OF COVID-19 PANDEMIC ON NEUROSURGICAL ONCOLOGY PRACTICES AT INOVA HEALTH SYSTEM: AN INSTITUTIONAL EXPERIENCE
Authors: Dang Danielle , Mugge Luke , Awan Omar , Gunnells Emily , Vaughan Megan , Ziu Mateo 
Published: December 2020

Abstract

INTRODUCTION
Amidst the unprecedented nationwide ban on elective surgeries during the COVID-19 pandemic, concern regarding timely and safe treatment of patients with intracranial tumors has been raised in the neuro-oncology community.

METHODS
A retrospective chart review was performed on all patients who underwent treatment for intracranial tumors from 3/12–7/1 for 2019 and 2020. Dates aligned with declaration of State of Emergency through the multi-phase public re-opening. Primary comparative endpoints included case volume, median time to surgery, chemotherapy, and radiation, and COVID-related mortality.

RESULTS
Overall surgical case volume decreased by 26.6%, while a 46.9% decrease was evident during the ban on elective surgeries. Case reduction occurred only for glial (p= 0.33) and pituitary tumors (p=0.04) where volume was nearly identical for other tumors. Median time to surgery was 2.5 days (range: 0–9) for high-grade glioma patients, 3 days for metastases, 3 days for meningiomas, and 26 days (range: 0–98) for pituitary adenomas, not significantly different from 2019. Time to chemoradiation and planned number of treatments were without significant difference. Among 2,795 Covid-19 patients treated in our institution, only four had brain tumors. Only one patient experienced delayed radiation treatment (three weeks) due to inability to achieve seroconversion prior to planned simulation. Only one COVID-related mortality in our cohort occurred.

DISCUSSION
The pandemic did not significantly delay type and time to treatment for neuro-oncology patients at Inova. With swift implementation of PPE and strict peri-operative testing, we provided standard of care treatment without increases in COVID-19 contraction or mortality. Decreases in overall case volume are likely due to ongoing cultural avoidance of seeking medical care; deferment of endonasal surgery may be attributed to a known greater mortality for ENT procedures. Future patient care challenges include establishing clinical significance of seroconversion for asymptomatic, COVID-19 infected patients without delaying necessary systemic treatment.
COVD-19. COGNITION, CANCER, AND COVID: DELIVERING DIRECT-TO-HOME TELE-NEUROPSYCHOLOGY SERVICES TO NEURO-ONCOLOGY PATIENTS
Authors: Gardner Melissa , Aslanzadeh Farah , Zarrella Giuliana , Braun Sarah , Loughan Ashlee , Parsons Michael 
Published: December 2020

Abstract

BACKGROUND
The COVID-19 pandemic altered the delivery of healthcare services globally with a rapid adoption of telemedicine to meet patient’s needs. Telemedicine is critical for neuro-oncology patients who may be at an increased risk of infection, yet require continuity of care. An important aspect of neuro-oncology care includes neuropsychological assessment, which can be challenging to complete outside of a structured testing environment. Teleneuropsychology (TNP) has been explored under proctored conditions and proven feasible and reliable. Conducting TNP visits directly to the patients’ home (DTH-TNP) had minimal study prior to the pandemic, but was implemented to reduce COVID-19 exposure.

METHODS
We used surveys to examine patient acceptance and clinician feasibility of DTH-TNP at two regionally diverse medical institutions routinely providing neuropsychological assessments services to neuro-oncology patients from April to August 2020, Massachusetts General Hospital (MGH) and Virginia Commonwealth University (VCU).

RESULTS
45 patients voluntarily responded (MGH=30, VCU=15) and 98 percent (MGH=100%, VCU=93%) of respondents were satisfied with the DTH-TNP experience. Nine percent (MGH=7%, VCU=13%) reported challenges (e.g., technological issues) during the appointment. Eighty-nine percent (MGH=90%, VCU=87%) would recommend the virtual visit to others. Patients perceived reduced risk of infection (MGH=77%, VCU=87%) and time traveling to clinic (MGH=87%, VCU=80%) as favorable aspects of DTH-TNP. 43 clinician surveys collected at MGH indicated that clinicians were able to achieve the goal of their appointment in 91% of clinical encounters. Common issues reported by clinicians included trouble connecting (7%) to the telemedicine platform and environmental disruptions (12%).

DISCUSSION
This preliminary data suggests neuro-oncology patients and clinicians find DTH-TNP to be an acceptable and feasible practice, while also recognizing its limitations. This study is limited in that voluntary patient surveys are subject to bias. These results suggest that further study of DTH-TNP (e.g., reliability, validity, and limitations) for neuro-oncology patients is warranted. Future directions are discussed.
COVD-26. TELEPHONE CONSULTATIONS IN NEURO-ONCOLOGY DURING THE COVID-19 PANDEMIC: LEVELS OF PATIENT SATISFACTION AND COMPARISON WITH TRADITIONAL FACE-TO-FACE CONSULTATIONS
Authors: Toman Emma , Goddard Claire , Berki Frederick , Garratt William , Scott Teresa , Sher Zenab , Stevens Andrew , Petrik Vladimir , Ughratdar Ismail , White Anwen , Zisakis Athanasios , Watts Colin , Wykes Victoria 
Published: December 2020

Abstract

INTRODUCTION
Controversy exists as to whether telephone clinics are appropriate in neurosurgical-oncology. The COVID-19 pandemic forced neuro-oncology services worldwide to re-design and at the University Hospitals Birmingham UK, telephone clinics were quickly implemented in select patients to limit numbers of patients attending hospital. It was important to determine how these changes were perceived by patients.

METHODS
A 20-question patient satisfaction questionnaire was distributed to patients who attended neuro-oncology clinic in person (“face-to-face”), or via the telephone. Fisher’s exact test was used to determine significance, which was set at p&lt; 0.05.

RESULTS
Eighty questionnaires were distributed between June 2020 and August 2020. Overall, 50% (n=40) of patients returned the questionnaire, 50% (n=23) of face-to-face and 50% (n=17) telephone patients. Of those who received telephone consultations, 88% (n=15) felt the consultation was convenient, 88% (n=15) were satisfied with their consultation and 18% (n=3) felt they would have preferred to have a face-to-face appointment. Of those who attended clinic in person, 96% (n=22) felt their consultation was convenient, 100% (n=23) were satisfied with their consultation and 13% (n=3) would have preferred a telephone consultation. Within the face-to-face clinic attendees, only 13% (n=3) were concerned regarding the COVID risk associated with attending hospital. There was no significant difference in patient convenience or satisfaction (p=0.565 and p=0.174 respectively) between face-to-face and telephone clinics. There was no significant difference in whether patients would’ve preferred the alternative method of consultation (p &gt; 0.999).

CONCLUSION
Our study suggests that careful patient selection for neuro-oncology telephone clinic is not inferior to face-to-face clinic. Telephone clinic during COVID-19 pandemic proved to be convenient, safe and effective. This global health crisis has transformed telephone neuro-oncology consultations from an experimental innovation into established practice and should be continued beyond the pandemic in select cases.
COVD-29. CONTINUATION OF TEMOZOLOMIDE CHEMOTHERAPY IN A GLIOBLASTOMA PATIENT AFTER RESOLUTION OF COVID-19 PNEUMONIA
Authors: Thakkar Jigisha , Teitcher Michael , Anderson Douglas , Barton Kevin , Melain Edward 
Published: December 2020

Abstract
We present a case of a 33 year-old patient with glioblastoma (IDH wild type, MGMT unmethylated) who was diagnosed with COVID-19 pneumonia while undergoing chemotherapy. The patient did not have any medical comorbidities. He was clinically asymptomatic following surgery, completed concurrent phase of combined chemotherapy and radiation and was undergoing treatment with adjuvant temozolomide. He had radiographic improvement of the brain tumor (decreased size, contrast enhancement and T2 flair) after three cycles of adjuvant temozolomide. However, after cycle three the patient developed fever and abdominal pain. Evaluation in the emergency room revealed low absolute lymphocyte count (0.7 K/MM3), positive COVID-19 point of care test and CT chest revealed patchy peripheral bibasilar ground glass and consolidative opacities compatible with pulmonary infection, with viral etiology such as COVID. Symptoms resolved after 2 weeks. Due to active infection and leucopenia temozolomide was on hold for 1 month. He was considered cleared of infection after resolution of symptoms. Temozolomide was initiated after resolution of leucopenia. Patient continued to do well after administration of subsequent temozolomide cycles and repeat CT chest after 2 months revealed resolution of consolidation and no new areas of consolidation. Temozolomide was safely administered in this patient without reactivation of COVID-19 infection. He did not have any thrombotic events.
CSIG-01. IDENTIFICATION OF PATHOGENESIS-RELEVANT microRNAs IN BRAIN METASTASIS
Authors: Mulcahy Elizabeth , Colon Rossymar , Zhang Ying , Gibert Myron , Kim Jungeun , Devairakkam Eric , Abounader Roger , Fadul Camilo 
Published: December 2020

Abstract
When brain metastasis develops, the prognosis of cancer is dismal. Insights into the biology of the primary cancer and the brain metastasis are necessary to inform more effective and targeted treatments. To study the role of microRNAs in brain metastasis, we performed differential expression profiling of 12 primary tumors and their paired brain metastases using smRNAseq (the 12 primary tumors included three non-small cell carcinomas, three melanomas, three endometrial carcinomas, one breast carcinoma, one thyroid carcinoma and one renal-cell carcinoma). To start, we identified microRNAs that were either highly upregulated or downregulated in the brain metastasis samples as compared to the paired primary tumors. After confirmation with real-time quantitative PCR, we further investigated the top microRNAs from both groups through functional assays performed in cell lines generated from primary melanoma, melanoma lymph node metastasis, and melanoma brain metastasis. From this top-down, patient sample to model cell-line approach we identified two microRNAs that are potentially important regulators in the development of brain metastasis. Characterization of their targets and their interactions may offer a therapeutic opportunity to improve the prognosis of patients with brain metastasis.