bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ionospheric effects in VLBI measured with space-ground interferometer RadioAstron
Authors: Popov M V , Bartel N , Burgin M S , Smirnova T V , Soglasnov V A 
Published: July 2021

ABSTRACT
We report on slow phase variations of the response of the space-ground radio interferometer RadioAstron during observations of pulsar B0329+54. The phase variations are due to the ionosphere and clearly distinguishable from effects of interstellar scintillation. Observations were made in a frequency range of 316–332 MHz with the 110-m Green Bank Telescope and the 10-m RadioAstron telescope in 1-h sessions on 2012 November 26, 27, 28, and 29 with progressively increasing baseline projections of about 60, 90, 180, and 240 thousand kilometres. Quasi-periodic phase variations of interferometric scintles were detected in two observing sessions with characteristic time-scales of 12 and 10 min and amplitudes of up to 6.9 radians. We attribute the variations to the influence of medium-scale Travelling Ionospheric Disturbances. The measured amplitude corresponds to variations in vertical total electron content in ionosphere of about $0.1\times 10^{16}\, \text{m}^{-2}$. Such variations would noticeably constrain the coherent integration time in VLBI studies of compact radio sources at low frequencies.
MOMC-1. Employing the Zika Virus to kill paediatric nervous system tumour cells
Authors: Sherwood Matthew , Ewing Robert , Kaid Carolini , Mitsugi Thiago Giove , Okamoto Keith 
Published: July 2021

Abstract
Malignant paediatric nervous system tumours, such as Medulloblastoma, Neuroblastoma and ATRT commonly harbour tumour cells with stem-like features which are highly tumorigenic and resistant to conventional cancer therapies. These tumours can exhibit high lethality and may result in severe sequelae, including cognitive and motor deficits that significantly affect patients’ quality of life. Oncolytic virotherapy is a novel therapy class that exploits viruses that preferentially infect and destroy tumour cells. These viruses present a unique advantage in targeting highly heterogeneous cancers, such as nervous system tumours, as they possess a secondary mechanism of action through which they induce a tumour-specific immune response. Clinical studies employing oncolytic virotherapy have in general reported low toxicity and minimal adverse effects, deeming oncolytic virotherapy as a potentially attractive and safer intervention against paediatric tumours.
The Zika virus (ZIKV) is capable of infecting and destroying neural stem-like cancer cells from human embryonal Central Nervous System (CNS) tumours in vitro and in vivo. Infection of CNS tumour cells with ZIKV effectively inhibits tumour metastasis in mice and, in some cases, induces complete tumour remission. Neuroblastoma arises from immature nerve cells and multiple Neuroblastoma cell lines are susceptible to ZIKV infection and oncolysis. These initial findings have demonstrated the potential for a ZIKV-based virotherapy against paediatric nervous system tumours and warrants examination into the molecular mechanisms through which ZIKV executes its oncolytic ability. My research goal is to elucidate the mechanisms which are of paramount importance for ZIKV-induced oncolysis of brain tumour and Neuroblastoma cells. Utilising global expression omics profiling of ZIKV infection and mapping of viral protein-host protein interactions will identify these mechanisms both at the cellular pathway and molecular levels. These collectively will inform our understanding of how we can employ a future ZIKV-based virotherapy against paediatric nervous system tumours.
NGMA-5. An in vivo functional genomics screen to identify novel drivers of lung-to-brain metastasis
Authors: Aghaei Nikoo , Lam Fred C , Kasper Ekkhard , Venugopal Chitra , Singh Sheila 
Published: July 2021

Abstract

Introduction
Brain metastases, the most common tumors of the central nervous system, occur in approximately 20% of primary adult cancers. In particular, 40% of patients with non-small cell lung cancer develop brain metastasis. As systemic therapies for the treatment of non-small cell lung cancer become increasingly effective at controlling primary disease, patients are ironically succumbing to their brain metastases. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). We hypothesize that an in vivo functional genomic screen can identify novel genes that drive LBM.

Methods
To do this, we developed a patient-derived xenograft (PDX) mouse model of LBM using patient lung cancer cell lines. This PDX model of LBM enables the use of fluorescent and bioluminescent in vivo imaging to track the progression of lung tumor and brain metastases.

Results
We have performed an in vivo genome-wide CRISPR activation screening to identify novel drivers of LBM. We will derive candidate genes through mouse brain and lung tissue sequencing after mice reach endpoint.

Expected Area of findings
This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer.

Conclusion
To the best of our knowledge, this is the first genome-wide in vivo CRISPR activation screen searching for drivers of LBM using a PDX animal model. This study can provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery.
OPTC-5. Molecular signatures of podoplanin expressing glioblastoma cell subsets with putative role in cancer associated thrombosis and microthrombosis
Authors: Tawil Nadim , Bassawon Rayhaan , Meehan Brian , Montermini Laura , Choi Dongsic , Nehme Ali , Najafabadi Hamed , Riazalhosseini Yasser , De Jay Nicolas , Kleinman Claudia , Gayden Tenzin , Spinelli Cristiana , Adnani Lata , Couturier Charles , Petrecca Kevin , Jabado Nada , Rak Janusz 
Published: July 2021

Abstract
Vascular anomalies, including thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of dysregulated cancer cell genome and epigenome. Upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk of venous thromboembolism in glioblastoma patients. Thus, regulation of this platelet activating transmembrane protein by transforming events and release from cancer cells into the circulation are of considerable interest. We took advantage of single-cell and bulk GBM transcriptome dataset mining and investigated the pattern of PDPN expression across several databases. Our analysis indicated that PDPN is expressed by distinct (mesenchymal) glioblastoma cell subpopulations and is downregulated by oncogenic mutations of EGFR and IDH1 genes, via changes in chromatin modifications (EZH2) and DNA methylation, respectively. Additionally, we utilized isogenic and stem GBM cell lines, xenograft models in mice, ELISA assays for PDPN, tissue factor (TF), platelet factor 4 (PF4) and clotting activation markers (D-dimer), and multicolor nano-flow cytometry to show that GBM cells exteriorize PDPN and/or TF as cargo of exosome-like coagulant extracellular vesicles EVs. We also documented an increase of platelet activation (PF4) or coagulation markers (D-dimer) in mice harboring the corresponding PDPN- or TF-expressing glioma xenografts, respectively. While PDPN was a dominant regulator of systemic platelet activation, co-expression of PDPN and TF impacted local microthrombosis. Our work suggests that distinct cellular subsets drive multiple facets of GBM-associated thrombosis and may represent targets for diagnosis and intervention.
OMRT-2. Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent glioblastoma
Authors: Yekula Anudeep , Kitchen Robert , Chakrabortty Sudipto , Carter Bob , Breakefield Xandra , Skog Johan , Balaj Leonora 
Published: July 2021

Abstract

Introduction
Liquid biopsy for the detection and monitoring of brain tumors is of significant clinical interest. The ability to non-invasively profile tumors can avoid a risky biopsy and opens avenues for testing novel therapies by accurately stratifying patients to receive the right therapy. Here, we provide evidence of EV RNA-based diagnosis, patient stratification, and assessment of response to therapy in the setting of a clinical trial evaluating the efficacy of dacomitinib, an EGFR tyrosine kinase inhibitor in patients with recurrent, EGFR amplified GBM(NCT01112527).

Methods
We performed RNASeq on long RNA extracted from the serum samples, pre-treatment and 1-month post-treatment.

Results
Firstly, longRNASeq allowed the detection of thousands of mRNA, lincRNAs and antisense RNAs enabling the study of a wider repertoire of potential RNA based biomarkers.
Secondly, we observed a differential expression profile in serum EV RNA of GBM patients and healthy controls. Combining our findings with TCGA data and literature screening, we generated a 25 gene signature representative of critical pathways in several hallmarks of cancer.
Thirdly, we observed a differential expression profile in serum EV RNA of responders to dacomitinib compared to non-responders in pre-treatment serum. Specifically, the EV mRNAs ZNF35 and LAMTOR2 distinguish responders from non-responders (p-adjusted = 2.6E-8 and 2.4E-6, respectively) allowing potential patient stratification.
Finally, we observed a differential expression profile in serum EV RNA of responders to dacomitinib compared to non-responders in post-treatment serum. EV mRNA DNMT3A is significantly enriched (p-adjusted = 1.8E-4) in post-treatment serum of responders compared to non-responders to dacomitinib allowing potential monitoring of response to therapy.

Conclusion
This study represents the first longitudinal profiling of the EV transcriptome in a cohort of genomically selected GBM patients. These findings are a tantalizing step toward liquid biopsy-based biomarkers for the detection of GBM, as well as patient stratification and monitoring.
OMRT-5. Therapy-induced reprogramming drives glioma vascular transdifferentiation and recurrence
Authors: Muthukrishnan Sree Deepthi , Kawaguchi Riki , Nair Pooja , Prasad Rachna , Qin Yue , Condro Michael , Wang Qing , Alvarado Alvaro , Kornblum Harley 
Published: July 2021

Abstract
Therapy-resistant glioma cells elicit remarkable phenotypic plasticity leading to aggressive tumor recurrence. Here, we used single-cell and whole transcriptomic sequencing to uncover that radiation treatment induces a dynamic shift in functional states of glioma cells allowing for acquisition of either stem-like, mesenchymal-like or vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is the vascular-like cell state, resulting in transdifferentiation to endothelial-like and pericyte-like cells in distinct cell clusters. The transdifferentiated endothelial-like and pericyte-like cells secrete trophic factors to support proliferation of tumor cells, and their selective ablation results in reduced tumor growth and recurrence post-treatment. Mechanistically, the acquisition of vascular-like phenotype is driven by increased acetylation and chromatin accessibility in vascular genes and in regions for binding of vascular specification transcription factors. Blocking histone acetylation using a small molecule inhibitor targeting P300 histone acetyltransferase activity prior to radiation treatment inhibits the vascular-like transdifferentiation of glioma cells and tumor growth. Our findings indicate that radiation therapy-induces rewiring of glioma cells that promotes vascular cell-like transdifferentiation, tumor growth and recurrence.
OMRT-6. Optimizing MDM2 inhibition for the treatment of high-grade glioma
Authors: Rendo Veronica , Lupien Leslie , Khuu Nicholas , Pelton Kristine , Lu Sophie , Khadka Prasidda , Langhnoja Jaldeep , Phoenix Timothy , Ligon Keith , Bandopadhayay Pratiti , Beroukhim Rameen 
Published: July 2021

Abstract
Over 80% of high-grade gliomas have alterations in members of the p53 pathway, a central regulator of cell cycle progression and apoptosis that becomes activated in response to cellular stress and DNA damage. For tumors that retain wild-type p53, pathway deregulation frequently occurs through the amplification of negative regulators of p53, including the E3 ubiquitin ligase MDM2. The p53/MDM2 interaction axis has served as basis for the development of several classes of MDM2 inhibitors, with AMG232 being the most potent molecule currently undergoing clinical evaluation. As the effects of MDM2 inhibition (MDM2i) remain poorly understood in high-grade glioma, we performed genomic and transcriptomic analyses in patient-derived models to better characterize sensitive tumors and identify putative biomarkers of drug response. Treatment with AMG232 impaired the growth of cell lines with wild-type p53 status, particularly in tumors with additional amplification of MDM4 or PPM1D activating mutations. Treatment with AMG232 upregulated both cell cycle arrest and apoptotic cellular responses, as measured by annexin V/PI staining and immunoblotting. Interestingly, the dynamics of these two downstream p53 signaling axis were dependent on treatment duration across models. In addition to p53 pathway activation and apoptotic induction, RNA-sequencing revealed MDM2i to be associated with the activation of oncogenic MAPK and KRAS signaling as well as epithelial to mesenchymal transition markers. In most solid tumors, resistance to MDM2i is mainly mediated by acquisition of p53 inactivating mutations. We hypothesized that resistance mechanisms in glioma may be partially driven by transcriptional changes, as these tumors consist of subpopulations with diverse cell differentiation states. By chronic AMG232 treatment, we have developed in vitro and in vivo models of acquired MDM2i resistance that are not mediated by p53 inactivation. Ongoing work is focused on characterizing the transcriptional profile of these cells to identify transcriptional changes leading to decreased drug response.
OMRT-7. Angiogenesis inhibitors strongly synergize with therapeutics targeting tumor metabolism
Authors: Khadka Sunada 
Published: July 2021

Abstract
Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their death. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit some degree of metabolic stress, this is stress is not sufficient to induce significant cancer cell death. We posit that the full potential of angiogenesis inhibition can be realized by the combination of angiogenesis inhibition with emerging tumor metabolism targeting therapies. Because tumors under angiogenesis inhibition are already in a state of nutrient stress, the effects of metabolically targeted therapies such as amino acid depletion (e.g. asparginase, methionine restriction), inhibitors of stress adaption (AMPK and GCN2 inhibitors) or energy metabolism (e.g. IACS-010759, Metformin, POMHEX) stand to dramatically increase in potency whilst remaining selective for (angiogenic) tumor versus (non-angiogenic) normal tissue. Here, we provide proof-of-principal for this thesis. First, we performed metabolomic profiling of angiogenesis-inhibited tumors, which corroborates a state of nutrient stress in angiogenesis-inhibited tumors. Second, we demonstrate dramatic anti-neoplastic synergy (effectively curing of xenografted tumor-bearing mice, irrespective of initial tumor size), without enhanced adverse toxicities, between the OxPhos inhibitor IACS-010759 and the angiogenesis tyrosine kinase inhibitor, Tivozanib. The same results were recapitulated with the anti-VEGFA antibody, Avastin, and the OxPhos inhibitor could be substituted with the Enolase inhibitor HEX, with similar effects. The synergy was observed in a broad range of tumor types, even those without clear genetic susceptibilities. Together, these results suggest that angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.
OMRT-9. Effect of Pre-Operative Stereotactic Radiosurgery on Brain Metastasis: Analysis of DNA and RNA Genomic Profiles from Phase-II Clinical Trial NCT03398694
Authors: Shireman Jack , Huff Wei , Monaco Gina , Agrawal Namita , Watson Gordon , Dey Mahua 
Published: July 2021

Abstract

Background
With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising and negatively impacting patient’s overall survival (OS). Treatment varies based on presentation, however, for patients with &lt;4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence in the follow-up period. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1–4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor.

Methods
Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. DNA and RNA were isolated from all samples for sequencing.

Conclusions
Our initial analyses show that pre-treatment with SRS, results in significant genomic changes at DNA and RNA levels throughout the tumor, in both center as well as periphery. Furthermore, significant transcriptomic differences were noted among matched samples between the central and peripheral SRS locations implicating differential effect of SRS dosing within a tumor. Initial gene ontological analysis on non-small cell lung cancer samples demonstrated an overexpression of WNT and BMP signaling pathways (p &lt;.001, p&lt;.01). These pathways are typically involved in neuronal development, hinting that adaptation to the brain microenvironment was occurring post SRS treatment.
OMRT-15. Multidisciplinary management of non-small cell lung cancer patients with leptomeningeal metastasis in the TKI era
Authors: Chen Kuan-Yu , Huang Abel Po-Hao 
Published: July 2021

Abstract

Background
leptomeningeal metastasis (LM) is a devastating scenario in patients with non-small cell lung cancer (NSCLC), with an estimated median overall survival (OS) of 4–6 months from diagnosis. Several studies have clarified the prognosis of treatment modalities after LM. However, just a few studies have clarified the prognosis of LM patterns. We evaluate the prognosis based on various patterns of LM under multidisciplinary treatment (MDT).

Method
This retrospective study evaluated NSCLC patients treated at National Taiwan University Hospital between 2007–2019 with brain metastases (BM) and LM. LM was classified into LM only, LM concurrent with BM, and LM after BM. Treatments including systemic therapy, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and intrathecal chemotherapy with Methotrexate (IT MTX) were recorded. BM excision was done by a neurosurgeon using minimally invasive neurosurgery. The MDT was done according to patients’ clinical situations. Kaplan-Meier methodology was used to describe overall survival OS. Multivariate Cox regression model was used to access prognostic factors.

Result
One hunderd patients with NSCLC CNS metastasis was included in this study. Median OS in patients with single, oligo and multiple BM was 42.0 months (95% CI= 0.12–83.89), 58.1 months (95% CI= 13.00–103.26), and 21.3 months (95% CI= 16.93–25.73), respectively. The median OS of all LM patients was 9.8 months. The median OS of LM after BM, concurrent BMLM, and LM only was 8 months (95% CI= 2.58–13.56), 41.5 months (95% CI= 0.00–94.36), and 18.5 months (95% CI=3.68–33.32), respectively. Multivariate Cox regression analysis showed only IT MTX (p= 0.010, HR= 0.392, 95%CI= 0.19–0.80) was associated with survival.

Conclusion
MDT in the TKI era has led to a dramatic improvement of OS in patients with LM (4–6 months vs. 9.8 months). NSCLC patients with LM only and concurrent BM LM has a better prognosis and longer survival, and thus are worth receiving intensive MDT care.
OTME-5. Meningioma liquid biopsy specimens exhibit contrasting immune-cell landscapes across methylation-subtypes and estimated recurrence risk subgroups
Authors: Herrgott Grayson , She Ruicong , Sabedot Thais , Wells Michael , Asmaro Karam , Malta Tathiane , Mosella Maritza , Nelson Kevin , deCarvalho Ana , Poisson Laila , Mukherjee Abir , Cazacu Simona , Robin Adam , Lee Ian , Snyder James , Walbert Tobias , Rosenblum Mark , Mikkelsen Tom , Kalkanis Steven , Rock Jack , Noushmehr Houtan , Castro Ana Valeria 
Published: July 2021

Abstract

Background
Tumor-infiltrating immune cell compositions have been previously correlated to encouragement or inhibition of tumor growth. This association highlights immune-landscape profiling through non-invasive methods as a crucial step in approaches to treatment of patients with meningioma (MNG), a prevalent primary intracranial tumor. Genome-wide DNA methylation patterns can aid in definition and assessment of cell compositions in liquid biopsy serum specimens, and allow for development of machine-learning models with predictive capabilities.

Methods
We profiled the cfDNA methylome (EPIC array) in liquid biopsy specimens from patients with MNG (n = 63) and nontumor controls (n = 6). We conducted both unsupervised epigenome-wide and supervised analyses of the meningioma methylome. Estimation of immune cell composition was conducted using Python-based methodology, where a reference methylome atlas of chosen cell types (B-cells, CD4- and CD8T-cells, neutrophils, natural killer cells, monocytes, cortical neuron, vascular endothelial cells, and healthy meninge) was used to deconvolute the MNG samples. Recurrence risk was estimated using an existing methylation-based Random-Forest classifier previously reported and validated, adapted to our serum-based cohort through employment of translatable meningioma subgroup-specific methylation markers (differentially methylated probes).

Results
We identified four distinct genome-wide methylation subgroups (k-clusters) of MNG which presented differential tumor micro-environments across all cell types investigated. Application of the DNA methylation-based Random-Forest classifier allowed for categorization of primary MNG serum samples into estimated recurrence-risk subgroups. Significantly contrasting micro-environments for the subgroups were observed across several cell-types, with those MNG more likely to recur displaying depletion in cell types reported to improve anti-tumoral response in many tumors (e.g. T-Cells).

Conclusions
DNA methylation based deconvolution allowed for detection of contrasting tumor microenvironment compositions across MNG methylation subtypes and recurrence-risk estimation subgroups. These results suggest that microenvironment profiling can be informative of probable tumor behavior and prognostic outcomes, helping guide therapeutic approaches towards treatment of patients with MNG.