bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards a scientific evaluation of environmental water offsetting in the Murray–Darling Basin, Australia
Authors: Lyons Kate , Pittock Jamie , Colloff Matthew J. , Yu Yilan , Rocheta Eytan , Steinfeld Celine
Published: November 2022

Context Increasing water scarcity creates the major challenge of how to achieve environmental outcomes while meeting human water demands. In the Murray–Darling Basin, Australia, this challenge is being addressed by the Murray–Darling Basin Plan and the ‘Sustainable Diversion Limit Adjustment Mechanism’ (SDLAM), an offsetting program seeking to achieve environmental outcomes using less water. Aims We provide a critique of the legislated method for evaluation of the SDLAM and the suitability of the process for evaluating whether equivalent environmental outcomes have been achieved. Methods Four project case studies, project documentation, external reviews and relevant legislation were used to assess the implementation of the SDLAM and the evaluation method. Key results The SDLAM evaluation method is not scientifically rigorous. It excludes residual risks, Basin-wide impacts and climate change. The evaluation timeline is biased towards measuring infrastructure outputs rather than environmental outcomes and impacts. Conclusions Flaws in the SDLAM evaluation processes mean that environmental benefits are likely to be overstated, risking further reductions in allocations of water for the environment, contrary to the objectives of the Basin Plan. Implications Improved evaluation, including empirical data on outputs, outcomes and impacts, is needed to ensure that conservation objectives can be met for wetlands subject to SDLAM projects.
Enhancing interprofessional practice through the co-design of a holistic culturally and developmentally informed First Nations child health assessment
Authors: Reid Natasha , Liu Wei , Morrissey Shirley , Page Marjad , McDonald Theresa , Hawkins Erinn , Wood Andrew , Parker-Tomlin Michelle , Myatt Grace , Webster Heidi , Greathead Bridget , Shelton Doug , Horton Sarah , Katsikitis Mary , Shanley Dianne
Published: November 2022

Background This qualitative study explored staff experiences of co-designing and implementing a novel interprofessional (IP) First Nations child health assessment (the helpful check), developed in partnership with a remote North-Queensland Aboriginal Community Controlled Health Organisation. Method Eleven staff across two teams (family health and allied health) were involved in co-designing and implementing the child health assessment and associated IP practices. Interviews were undertaken using a semi-structured interview template and were audio recorded and transcribed verbatim. Data were analysed using thematic analysis. Results Three overarching themes were developed: (1) connect teams by building strong relationships; (2) leave space for helpful check processes to evolve; and (3) integrate helpful check processes into routine practice to sustain change. Conclusions Results demonstrate how the incorporation of IP practices into a remote primary healthcare setting led to perceived benefits for both the health service staff and clients.
A corpus-driven exploration of conspiracy theorising as a discourse type
Authors: Catenaccio Paola
Published: November 2022

This chapter takes a view of conspiracy theorising as a discourse type and seeks to identify candidate linguistic features of such discourse in a corpus of books devoted to 9/11 conspiracy theories. Adopting a corpus-driven approach, the study identifies three discursive traits which appear prominent in conspiracy discourse. The first trait concerns a high incidence of metadiscursive references to terms such as report, version and story, which are associated with negatively evaluative verbs (for example, claim) when premodified by the adjective official, and tend to co-occur with verbs such as emerge when referring to conspiracy theorists’ preferred versions. The second regards the frequent recourse to terms such as evidence (lack of which characterizes official stories) and facts (typically posited to be at the heart of conspiratorial versions). Finally, the study identifies the salience of hypothetical structures, signalled by the recurrent use of the modal would, which question official accounts using a modus tollens form of confutational argumentation.
“Go ahead and ‘debunk’ truth by calling it a conspiracy theory”
Authors: Garcés-Conejos Blitvich Pilar , Lorenzo-Dus Nuria
Published: November 2022

To help fill in the research gap on conspiracy theorizing online (Varis 2019), this chapter addresses two research questions: the discursive construction of conspiracy theoryness in online affinity spaces (Gee 2005) and the extent to which these discursive constructions are aligned with those previously identified by extant literature, which has traditionally taken a top-down, macro-level perspective, as defining of conspiracy theories. Conspiracy theories are essentially social constructs (Butter and Knight 2016). To our knowledge, research to date has not examined how notions of what counts as a conspiracy theory are shaped in a bottom-up manner as knowledge, identities, and associated practices that are subjected to discursive struggle. Online affinity spaces, such as those provided by Reddit and YouTube and in which conspiracy theories are regularly discussed, give us unprecedented access to this process. Our analysis shows how the discursive construction of knowledge is crucially related to the concept of truth and how, contrary to common representations, conspiracy theories are seen – from an emic perspective – as stemming from rationality, reasoning, and deployment of an (albeit sui generis) scientific method. Although committed to knowledge activism, conspiracy theories in our data display a manifest proclivity for eudaimonic and social variables and lean strongly towards the depiction of the agents’ identity (both human and non-human) against whom conspiracy theorists relationally construct who they are.
Exploring the echo chamber concept
Authors: Bondi Marina , Sanna Leonardo
Published: November 2022

Echo chambers have often been analyzed in social media studies as dysfunctions of communication fostering the polarization of debates and the spreading of conspiracy theories. On the other hand, from a linguistic perspective, very little research has been conducted on these themes. Our work aims to investigate the linguistic dimension of echo chambers, exploring them as ideological structures that are observable when ideological conflict occurs. Using word embedding and corpus-based discourse analysis, we investigate mediatic discourse on COVID-19 in the Coronavirus Corpus and in the Public Coronavirus Twitter Data Set. The analysis focuses on the semantic and pragmatic status of the word hoax, which emerges as a keyword characterizing the Twitter dataset. Our study shows how linguistic markers of ideological conflict can act as markers of position and affective/social identity.
Complementary concepts of disinformation
Authors: Seargeant Philip
Published: November 2022

This chapter looks at the relationship between two distinct but related forms of disinformation currently widespread in political discourse: ‘fake news’ and conspiracy theories. Both play a significant role in the promotion and circulation of forms of false information which are considered by many as a threat to civil society. They are both frequently co-opted as means of political persuasion, often for propaganda purposes. Despite their similarities, the two exist as distinct genres of disinformation. The aim of the chapter is to analyse the nature of their similarities and differences as rhetorical tools in order to provide a more nuanced picture of the role they both play in contemporary politics.
Properties and modification of native oxides of InP(100)
Authors: Ebrahimzadeh Masoud , Vuori Sami , Miettinen Mikko , Lehtiö Juha-Pekka , Granroth Sari , Punkkinen Marko P J , Rad Zahra Sadat Jahanshah , Punkkinen Risto , Kuzmin Mikhail , Laukkanen Pekka , Lastusaari Mika , Kokko Kalevi
Published: November 2022

Properties of oxidized InP surfaces, which are known to cause less electrical and optical losses than other III–V oxides, are relevant to develop the passivation of current and future applications of III–V crystals (e.g. lasers, detectors). We report that a proper low-temperature (LT) (<400 °C) gas exposure with NH3 or O2 enables beneficial modifications of InP native oxides, of which formation is difficult to avoid in devices. Effects of the gas exposure depend on the doping of InP. NH3 exposure without a plasma source at 250 °C or lower temperature increases photoluminescence (PL) intensity of native-oxide covered n-InP crystals, which interestingly provide a stronger PL signal than n-InP with the HCl-cleaned surface. In contrast, O2 exposure around 300 °C increases PL signal of native-oxide covered p-type InP. Core-level photoelectron spectra reveal that N atoms are incorporated into the native oxide system of InPO4/InP during LT NH3 exposures. Scanning tunneling microscopy shows a band bending and a tendency to crystallization at native-oxide covered InP surfaces. Photoelectron spectra, which are analyzed with recent calculations, show larger variation in the bonding environment for the host In atoms and for incorporated N atoms, as compared to the P bonding sites in the InPO4 native oxide.
Revisiting the involvement of tau in complex neural network remodeling: analysis of the extracellular neuronal activity in organotypic brain slice co-cultures
Authors: Bouillet Thomas , Ciba Manuel , Alves Caroline Lourenço , Rodrigues Francisco Aparecido , Thielemann Christiane , Colin Morvane , Buée Luc , Halliez Sophie
Published: November 2022

Objective. Tau ablation has a protective effect in epilepsy due to inhibition of the hyperexcitability/hypersynchrony. Protection may also occur in transgenic models of Alzheimer’s disease by reducing the epileptic activity and normalizing the excitation/inhibition imbalance. However, it is difficult to determine the exact functions of tau, because tau knockout (tauKO
) brain networks exhibit elusive phenotypes. In this study, we aimed to further explore the physiological role of tau using brain network remodeling. Approach. The effect of tau ablation was investigated in hippocampal-entorhinal slice co-cultures during network remodeling. We recorded the spontaneous extracellular neuronal activity over 2 weeks in single-slice cultures and co-cultures from control and tauKO
mice. We compared the burst activity and applied concepts and analytical tools intended for the analysis of the network synchrony and connectivity. Main results. Comparison of the control and tauKO
co-cultures revealed that tau ablation had an anti-synchrony effect on the hippocampal-entorhinal two-slice networks at late stages of culture, in line with the literature. Differences were also found between the single-slice and co-culture conditions, which indicated that tau ablation had differential effects at the sub-network scale. For instance, tau ablation was found to have an anti-synchrony effect on the co-cultured hippocampal slices throughout the culture, possibly due to a reduction in the excitation/inhibition ratio. Conversely, tau ablation led to increased synchrony in the entorhinal slices at early stages of the co-culture, possibly due to homogenization of the connectivity distribution. Significance. The new methodology presented here proved useful for investigating the role of tau in the remodeling of complex brain-derived neural networks. The results confirm previous findings and hypotheses concerning the effects of tau ablation on neural networks. Moreover, the results suggest, for the first time, that tau has multifaceted roles that vary in different brain sub-networks.
Phonon mediated superconductivity in field-effect doped molybdenum dichalcogenides
Authors: Marini Giovanni , Calandra Matteo
Published: November 2022

Superconductivity occurs in electrochemically doped molybdenum dichalcogenides samples thicker than four layers. While the critical temperature (T

c
) strongly depends on the field effect geometry (single or double gate) and on the sample (MoS2 or MoSe2), T

c
always saturates at high doping. The pairing mechanism and the complicated dependence of T

c
on doping, samples and field-effect geometry are currently not understood. Previous theoretical works assumed homogeneous doping of a single layer and attributed the T

c
saturation to a charge density wave instability, however the calculated values of the electron–phonon coupling in the harmonic approximation were one order of magnitude larger than the experimental estimates based on transport data. Here, by performing fully relativistic first principles calculations accounting for the sample thickness, the field-effect geometry and anharmonicity, we rule out the occurrence of charge density waves in the experimental doping range and demonstrate a suppression of one order of magnitude in the electron–phonon coupling, now in excellent agreement with transport data. By solving the anisotropic Migdal-Eliashberg equations, we explain the behavior of T

c
in different systems and geometries. As our first principles calculations show an ever increasing T

c
as a function of doping, we suggest that extrinsic mechanisms may be responsible for the experimentally observed saturating trend.
Decoherence of a spin-valley qubit in a MoS2 quantum dot
Authors: Arfaoui Mehdi , Jaziri Sihem
Published: November 2022

Transition metal dichalcogenide (TMD)-based quantum dots (QDs) have proven to be a successful and promising device for physically implementing electron spin-valley based qubits. Although the electron spin in a TMDs monolayer semiconductor QD can be isolated and controlled with high precision, decoherence occurs due to unavoidable coupling with the surrounding environment, such as nuclear spin environments. In this paper, using an exact master equation (ME) of spin qubit dynamics coupled to a nuclear spin bath in terms of hyperfine interaction (HI), we have investigated the controllability of dynamics processes with varying degrees of non-Markovianity. In large magnetic fields, we show that pure spin or valley qubits can be created. We calculate the loss of fidelity due to the Overhauser field of HI in a wide range of nuclear spin

N

. In this context, we prove that this field restricts the decoherence process of the central electron spin, which can regain its coherence. Finally, we discuss how the coherence of the spin qubit remains robust for large

N

.
Utilization of bictegravir/emtricitabine/tenofovir alafenamide in patients with end-stage renal disease on hemodialysis
Authors: Sidman Eric F , Ondrush Nicole M
Published: November 2022

Purpose

The combination antiretroviral bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is a single-tablet, once-daily regimen used in individuals living with HIV; however, its use in the context of renal impairment is uncertain. We report 6 patient cases of BIC/FTC/TAF utilization in individuals with HIV with end-stage renal disease (ESRD) requiring long-term hemodialysis (HD).

These case reports describe the utilization of BIC/FTC/TAF in individuals with HIV who require chronic HD, the laboratory parameters measured, and patient-reported quality of life and adverse events.

Conclusion

Utilization of BIC/FTC/TAF appears to be an option for individuals with HIV who have ESRD and require long-term HD. This regimen allows for once-daily dosing, elimination of potential serious drug interactions, and simplified patient ART regimens in our patient subset.
Application of DRGs in hospital medical record management and its impact on service quality
Authors: Zhang Qin , Li Xiaodong
Published: November 2022

Background

To explore the application of diagnosis-related groups (DRGs) in hospital medical record management and the impact on service quality.

Objective

This study introduced DGRs management into hospital medical record management in order to improve the quality of hospital medical record management.

Method

The medical record management of our hospital was analysed retrospectively between August 2020 and April 2021. A total of 7263 cases without DRG management before January 2021 were included in a control group, and 7922 cases with DRG management after January 2021 were included in a study group. The error rate of medical records, the specific error items and the scores of service capability, service efficiency and service quality were compared along with the comprehensive scores of the two groups.

Results

The error rate of medical records in the study group was significantly lower than that in the control group (19.35% vs. 31.24%, P < 0.05). The error rates in terms of diagnosis on admission, surgical procedures, main diagnosis and other diagnoses in the study group were significantly lower than those in the control group. The scores for service ability, service efficiency and service quality were significantly higher in the study group than in the control group (P < 0.05). The comprehensive evaluation score of the study group was significantly higher than that of the control group (P < 0.01).

Conclusion

Applying DRGs in the hospital medical record management can effectively reduce the error rate of medical records and improve the quality of hospital services.
A Primer on Chimerism Analysis: A Straightforward, Thorough Review
Authors: Morris Anna B , Bray Robert , Gebel Howard M , Cliff Sullivan H
Published: November 2022

Short tandem repeat (STR) analysis to assess chimerism is a critical aspect of routine care particularly in patients facing stem cell transplants but is also relevant in other clinical scenarios. STR analysis provides a means to assess donor and recipient cellular origins in a patient, and, as such, can inform engraftment, rejection, and relapse status in stem cell transplant recipients. In this review of STR testing, the most commonly used method to assess chimerism, its background, procedural details, and clinical utility are discussed.
Likelihood ratio to evaluate handwriting evidence using similarity index
Authors: Wydra Jȩdrzej , Matuszewski Szymon
Published: November 2022

Previous methods to evaluate evidence from handwriting examinations were usually associated with a redefinition of how these examinations are to be made. Here we propose the likelihood ratio method for handwriting evidence evaluation which is fully compatible with the current handwriting examination protocols. The method is focused on the similarity between handwriting samples, quantified using Jaccard index from results of a usual forensic handwriting comparison. The numerator of the likelihood ratio is the probability of a given class of similarity, assuming that a given person wrote the questioned sample. The denominator is the probability of the same class of similarity, assuming that a randomly selected person wrote questioned sample. The similarity distribution to quantify the numerator is derived from comparisons across reference handwritings. To calculate the denominator we propose to develop similarity distributions relevant for particular forensic scenarios. In the proof-of-a-concept study, we developed the distribution for the simulation scenario.
ANGI-01. METASTATIC ESTHESIONEUROBLASTOMA RECURRENCE AFTER 19 YEARS OF REMISSION: A SYSTEMATIC REVIEW WITH CASE ILLUSTRATION
Authors: Mozaffari Khashayar , Pradhan Anjali , Patel Kunal , Vivas Andrew , Yang Isaac
Published: November 2022

INTRODUCTION

Esthesioneuroblastoma (ENB) is a rare malignant neoplasm of the olfactory epithelium with an estimated incidence of 0.4/million. It can directly extend along the cribriform plate in order to metastasize to the central nervous system. However, non-contiguous intracranial involvement without recurrence at the primary site is extremely uncommon. In this report, the authors review the literature and present a case of non-contiguous intracranial metastasis of ENB without recurrence at the primary site. To the best of our knowledge, this case presents the longest disease-free interval reported in the literature.

METHODS

A systematic review of literature was conducted in accordance with the PRISMA guidelines. Additionally, the presentation, surgical management, and post-operative outcomes of an 82-year-old female with non-contiguous intracranial metastasis of ENB after 19 years of remission are described.

RESULTS

A total of 137 deduplicated works were identified after the search. Of these, 6 papers satisfied our inclusion criteria for our systematic review. Average age at presentation was 50.8 years (range: 26-66) and 52.6% of patients were female. A majority of cases achieved gross-total resection and received adjuvant radiotherapy for initial treatment. The median interval to intracranial metastasis was 6 years from the time of primary tumor presentation. The median overall survival from ENB recurrence with non-contiguous intracranial metastasis was 12 months.

CONCLUSIONS

ENB is a highly recurrent tumor and harbors the potential to involve the intracranial space even years after remission. Intracranial involvement entails poor overall survival. Lifetime radiographic follow-up should be considered in all patients with ENB.
ANGI-08. EPIGENETIC REACTIVATION OF BAI1 SUPPRESSES TUMOR INVASION, RECURRENCE, AND SPINAL METASTASIS BY PREVENTING TGFΒ1-INDUCED MESENCHYMAL SWITCH IN GLIOBLASTOMA
Authors: Osuka Satoru , Yang Liquan , Hashimoto Hideharu , Zhu Dan , Zhang Zhaobin , Olson Jeffrey , Devi Narra , Van Meir Erwin
Published: November 2022

Glioblastoma (GBM) is the most common and lethal type of malignant brain tumor in adults. GBM cells spread extensively in the brain and disseminate into the cerebrospinal fluid space, strongly restricting multimodal therapies. Acquiring a better knowledge of molecular defects underlying GBM invasion is essential for developing effective treatments.Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is a transmembrane receptor of the adhesion GPCR family widely expressed in the normal brain, but its expression is lost in the majority of GBM through epigenetic silencing and restoration of its expression can inhibit glioma growth. However, whether BAI1 loss is important for tumor invasion and the mesenchymal phenotype in GBM has not been investigated.Microarray analysis of the GBM TCGA dataset (restricted to IDHwt GBM; WHO 2021) revealed that low BAI1 mRNA expression correlates with elevated expression of many mesenchymal genes. Restoration of BAI1 expression in human GBM cells suppresses mesenchymal gene expression in culture and dramatically decreases brain tumor invasion in mice xenografts. Mechanistically, we found that the N-terminal thrombospondin type 1 repeat (TSR#1) of BAI1 inhibits the maturation process of TGFβ1, a key growth factor involved in EMT. BAI1 is silenced epigenetically in GBM cells by methylated CpG-binding protein MBD2, and its expression can be reactivated by KCC-07, a blood-brain barrier permeable MBD2 inhibitor. We found that restoration of BAI1 expression by KCC-07 treatment dramatically suppresses cell invasion in the brain and reduces leptomeningeal dissemination of GBM cells to the spine in mouse xenografts.These experiments demonstrate that epigenetic silencing of BAI1 is important for activating the GBM invasive phenotype through TGFβ1 pathway activation. This new tumor-suppressive pathway can be epigenetically targeted to reactivate BAI1 expression in GBM patients.
BIOM-02. MUTATIONAL ANALYSIS AND SINGLE CELL SEQUENCING OF MELANOMA BRAIN METASTASES REVEALS BRAF STATUS CORRELATES WITH CLINICAL OUTCOME AND DIFFERENTIAL IMMUNE POPULATIONS
Authors: Vasudevan Harish , Delley Cyrille , Aabedi Alexander , Shukla Poojan , Nguyen Minh , Morshed Ramin A , Young Jacob S , Demaree Ben , Diwanji Devan , Hervey-Jumper Shawn L , Boreta Lauren , Fogh Shannon , Nakamura Jean , Theodospoulos Philip , Phillips Joanna J , Daras Mariza , Tsai Katy , Sneed Penny , Aghi Manish , Raleigh David , Braunstein Steve , Abate Adam
Published: November 2022

Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p< 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p< 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.
BIOM-13. MICROPERFUSION-MEDIATED SOLUBLE EXTRACELLULAR ENVIRONMENT ANALYSIS FOR DETERMINATION OF CHEMOTHERAPEUTIC EFFICACY IN BRAIN TUMORS
Authors: Olson Ian , Zolp Andrew , Ventarapragada Divya , Miska Jason , Ahmed Atique
Published: November 2022

Glioblastoma (GBM) is the most prevalent and lethally recurrent central nervous system neoplasm, but its therapeutic advancement has stagnated for over 15 years. One major hurdle in front of clinical breakthroughs has been the relative lack of real-time, treatment-responsive biomarkers that occur during therapy. The methods of microdialysis and microperfusion, now entering both clinical and pre-clinical settings, offers an opportunity to overcome this hurdle by providing real-time, biologically relevant monitoring of the tumor microenvironment (TME). The goal of this project is to identify changes in the soluble extra-cellular regional environment of the tumor (SECRETome) of GBM in response to standard-of-care treatments using intra-tumoral microperfusion. In this study, we evaluated the response of murine GBM tumors to temozolomide (TMZ) during therapy by combining transcriptional changes to metabolic phenotypes obtained from SECRETome analysis. Our data demonstrated a 2-fold increase in levels of microperfusion-sampled 2-hydroxyglutarate (2-HG) on day 3 post-TMZ therapy as compared to untreated tumors. This expression is correlated with our RNAseq analysis wherein we observed an >600 fold increase in malate dehydrogenase 1 (MDH1 - an enzyme that converts alpha-ketoglutarate to 2-HG) on Day 4 post-TMZ treatment (p = 4.20e-04) as compared to untreated tumors. Therefore, we found that interstitial elevation of a TMZ-associated metabolite can be used to probe the genetic changes that occur within GBM during therapy. This proof-of-concept study demonstrates that microperfusion-mediated TME sampling can be used to understand the complex biological responses process that occurs during GBM chemotherapy, and may provide unique insights into how to better treat these tumors in the future. Moreover, the future establishment of clinical intra-operative microdialysis/microperfusion can be extrapolated to improve the pace of clinical therapeutic translation through homologous, treatment-responsive biomarkers in humans.
BIOM-16. A MULTI-OMIC, FUNCTIONAL PRECISION ONCOLOGY METHOD TO IDENTIFY RESPONSIVE GLIOBLASTOMA TUMOR CELLS AT SINGLE CELL RESOLUTION
Authors: De Visser Yanti , Panovska Dena , Cole Basiel , Hermans Lotte , Martinez Asier Antoranz , Nazari Pouya , Van Trimpont Maaike , Derweduwe Marleen , Claeys Annelies , De Vleeschouwer Steven , Solie Lien , Clement Paul , Sciot Raf , Verfaillie Michiel , Daenekindt Thomas , Bamps Sven , Van Vlierberghe Pieter , De Smet Frederik
Published: November 2022

Glioblastoma remains a highly malignant and intrinsically resistant brain tumor. Despite intensive research through which numerous potential druggable targets were identified, virtually all clinical trials of the past 20 years failed to improve the outcome for the vast majority of GBM patients. However, the identification of small subgroups of patients that showed an exceptional response across several trials, implies that, when selected more carefully, some GBM patients could probably still benefit from these therapies. Identifying these patients requires that suitable biomarkers are identified. In this project, we reassessed the molecular mechanisms of ten actionable compounds (selected from previously failed trials but for which exceptional responders had been observed) in a set of carefully selected patient-derived cell lines that were sensitive/resistant to the selected therapies. Moreover, to deal with tumor heterogeneity, we used a multi-omic functional precision oncology approach, combining scRNA-seq and CyTOF, to identify drug-specific biomarkers by comparing control and treated samples at single-cell resolution. By subsequently correlating the molecular signatures to eventual cytotoxicity profiles, we could identify intrinsically responsive tumor cells at the single-cell level within hours following drug exposure. Overall, this work lays the foundation for an actionable functional diagnostic assay that could help to identify eligible GBM patients in future clinical trials.
BIOM-17. SPYING ON GLIOMAS: LONGITUDINAL CSF AS A PLATFORM FOR GLIOMA MONITORING AND RESPONSE BIOMARKER DISCOVERY
Authors: Riviere-Cazaux Cecile , Ikram Samar , Chantigian Siobhan , Rahman Masum , Warrington Arthur , Burns Terry
Published: November 2022

The relative inaccessibility of a patient’s glioma throughout their disease course precludes individualized insights into tumor biology and responses thereof to therapeutic challenge. We propose that serial cerebrospinal fluid (CSF) samples can be used to perform glioma espionage in the form of biomarker discovery for analytes that are sensitive to tumor burden (for monitoring) and candidate therapies (for biological impact). To that end, we are routinely leveraging neurosurgical access to the CNS to collect CSF samples intraoperatively and from chronically implanted Ommaya reservoirs for longitudinal CSF access (NCT04692337, NCT04692324). 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. Using each patient’s ranked protein list (glioma vs. 3 control patients), enrichment analysis was performed in a discovery cohort of five patients to identify conserved proteins of glioma. To reveal candidate glioma monitoring, further enrichment analysis was performed to identify proteins that decreased with resection and increased with recurrence, using two sets of paired patient samples. Forty-four proteins met these enrichment criteria; this candidate high-grade glioma proteomic signature was highly significantly enriched in an independent cohort of twelve glioma patients (FDR=0 for all patients). The HGG signature decreased in abundance following resection in serial samples from two other patients, confirming decreased tumor burden. Top proteins included LANC2, DPYL3, Sorcin, Integrin A1B1, and lactate dehydrogenase (FC of glioma vs. control: 145.3x, 113.9x, 78.0x, 71.6x, and 62.7x, respectively). Interestingly, despite having explicitly chosen samples with little-to-no hemoglobin in the discovery cohort, this HGG signature was highly enriched for plasma-like proteins (FDR=0), suggesting a potential biological impact of blood-brain barrier disruption on the glioma extracellular proteome. In conclusion, our data demonstrate that the glioma extracellular proteome can feasibly be accessed to perform biomarker discovery (“espionage”) via serially-acquired CSF samples.
BIOM-18. CLINICOGENOMIC PREDICTORS FOR THE PATTERN OF FAILURE IN HIGH-GRADE GLIOMA
Authors: Kang Byung-Hee , Ho Lee Joo , Kim Tae Min , Yun Hongseok , Won Jae-Kyung , Choi Seung Hong , Lee Soon-Tae , Park Sung-Hye , Park Chul-Kee
Published: November 2022

Background

High-grade gliomas, the most common primary brain tumors, are highly lethal and treatment options remain limited. Despite advances in genomic technologies, there are few molecular biomarkers to guide precision medicine for high-grade glioma. Here, we aimed to identify the clinicogenomic features associated with its prognosis and recurrence patterns.

MATERIALS/METHODS

Our single-institution retrospective analysis included 182 patients diagnosed with high-grade gliomas who underwent next-generation sequencing targeting 82 brain tumor-relevant genes. Clinicopathological status, treatment characteristics, survival, and genomic profiles were analyzed.

RESULTS

At a median follow-up of 23 months (range, 2-229 months), 151 patients (83%) had progression or recurrences. Local and distant recurrences were observed in 132 (72.5%) and 101 (54.9%) patients, respectively. The most common genomic variants in high-grade gliomas were TP53 (42.9%), IDH1/2 (23.1%), TERT promoter (38.5%), ATRX (13.2%), H3F3A (7.1%), and SETD2 (6.0%) mutation. Regarding copy number variants, amplification of EGFR (20.9%), PDGFRA (9.9%), MYCN (2.2%) and loss of CDKN2A/2B (49.5%), PTEN (37.9%), RB1 (17.6%), and 1p19q codeletion(9.3%) were the most common copy number aberrations. On multivariate cox regression anlalysis, MYCN amplification (HR 6.08 95% CI 1.91-19.35, p = 0.002), and SETD2 mutation (HR 0.19 95% CI 0.06-0.62, p =0.06) were independent predictors of overall survival, in relation to previously established prognostic factors including age, Eastern Cooperative Oncology Group Performance Status (ECOG PS) scale, extent of resection, MGMT promoter methylation, and IDH1/2 mutation. Interestingly, MYCN amplification (HR 5.24 95% CI 1.69-16.27, p = 0.004), SETD2 mutation (HR 0.35 95% CI 0.12-0.99, p =0.048) were independent predictors of failure from distant recurrences.

CONCLUSION

The assessment of genomic characteristics in conjunction with pattern of failure for high-grade glioma aids to identify patients who are likely to benefit from personalized medicine. We identified SETD2 mutation, and MYCN as a prognostic biomarkers with potential therapeutic implications in patients with high-grade glioma.
BIOM-21. THE EFFECTIVENESS OF CIRCULATING MICRO RNAS DERIVED FROM GLIOBLASTOMA AS A BIOMARKER FOR EARLY DIAGNOSIS AND PROGNOSIS
Authors: Joo Park Hyun , Hwang Kihwan , Kwon Ji-Eyon , Han Ji Yun , Park Kyoung Un , Hong Yong-Kil , Kim Chae-Yong
Published: November 2022

BACKGROUND

Glioblastoma is the most common primary intracranial malignancy in adults. In cases where biopsy is not feasible due to tumors in inoperable locations including the brainstem, biomarkers such as micro RNA-21 (miR-21) extracted from blood samples could be utilized for diagnostic or prognostic purposes. In this study, we examined the role of miR-21 as a diagnostic factor in patients with glioblastoma.

METHODS

Inclusion criteria included patients with age greater than 20 years and with histologic confirmation of diagnosis. The blood samples were collected prior to surgery, after surgical resection, after concurrent chemoradiotherapy, and after 3 cycles of adjuvant temozolomide therapy. Using TaqMan assay, we extracted miR-21 from blood samples and compared its level with tumor volume on brain magnetic resonance imaging (MRI) scans. miR-21 levels before and after treatments were compared within each subject.

RESULTS

Eleven newly diagnosed glioblastoma patients were enrolled in this study, and final analyses were performed for eight patients with complete follow up serum samples. Two patients with stable disease after treatment displayed a decrease in miR-21 levels. Three out of four subjects with increase in miR-21 showed progressive disease on MRI scans. One patient with stable disease and an increased miR-21 level experienced postoperative intracranial hemorrhage and ischemic event. The two patients with unchanged miR-21 levels showed stable disease.

CONCLUSION

miR-21 levels were associated with progressive disease in glioblastoma patients. miR-21 has potential be utilized as a diagnostic marker in patients with glioblastoma, and further studies are needed to elucidate its role as a prognostic marker.
BIOM-25. DETERMINATION OF LEVELS OF SMALL MOLECULAR WEIGHT THIOLS AND DISULFIDES IN MOUSE AND HUMAN NORMAL BRAIN AND GLIOBLASTOMA TISSUE
Authors: Shaik Kamal , Margaryan Tigran , Sanai Nader , Tovmasyan Artak
Published: November 2022

BACKGROUND

Small molecular weight (SMW) thiols play an essential role in many biochemical processes, particularly in maintaining redox homeostasis. Herein, we report on the development and qualification of a sensitive and rapid LC-MS/MS method for the determination of oxidative stress biomarkers glutathione (GSH), cysteine (Cys), glutathione disulfide (GSSG), cystine (CySS), as well as the interrelated precursors and products methionine (Met), homocysteine (Hcy), cystathionine (Cysth), gamma glutamyl-cysteine (Glu-Cys), and cysteinylglycine (Cys-Gly) in both mouse and human normal brain and glioblastoma tissue.

METHODS

Mouse and human tissue samples were homogenized with N-ethylmaleimide solution to prevent thiol oxidation. Analytes were then extracted from homogenate samples by protein precipitation with 2% formic acid in acetonitrile. Separate calibration curves were prepared for thiols and disulfides in analytical solutions using stable isotope-labeled internal standards (IS). Three levels of quality control samples were prepared in mouse and human brain homogenates. The detection was performed on Sciex QTRAP 6500+ mass spectrometer in positive electrospray ionization mode.

RESULTS

The concentration ranges of 0.04-40 µmol/L for Glu-Cys/Hcy, 4-400 µmol/L for Met/GSH/Cys/Cys-Gly and 0.05-20 µmol/L for GSSG/CySS/Cysth were established using a linear regression model. A gradient elution was applied on Intrada Amino Acid column to achieve the optimal chromatographic separation with a 5 minute total run time. At least three precision and accuracy runs were conducted on different days. The stability of analytes in biological matrix and in analytical solutions has been tested at room temperature, 4 °C, and -80 °C for appropriate sample preparation, analysis, and storage.

CONCLUSIONS

A bioanalytical method to quantify a panel of SMW thiols and disulfides has been successfully developed, qualified, and utilized to assess the levels of these biomolecules in mouse normal brain and glioblastoma tissue as well as in glioblastoma tissue of patients enrolled in the sonodynamic therapy clinical trial (NCT04559685).
BIOM-30. ANALYSIS OF GLIOMA-RELATED GENES USING A BREAKTHROUGH AMPLIFICATION TECHNIQUE FOR CELL-FREE DNA IN CEREBROSPINAL FLUID
Authors: Adachi Jun-ichi , Mishima Kazuhiko , Nishikawa Ryo
Published: November 2022

BACKGROUND

In the pathological classification of brain tumors, newly revised in 2021, molecular genetic analysis of gliomas has become more important for diagnosis and understanding of the pathogenesis of the disease. Gliomas are prone to recurrence and malignant progression, and collecting tumor tissue during every genetic analysis is highly invasive. Therefore, techniques have been developed to analyze tumor-derived circulating cell-free DNA (ccfDNA) in the cerebrospinal fluid as a substitute for tissue collection. However, the amount of ccfDNA derived from the cerebrospinal fluid is extremely small and the number of cases for whom genetic analysis is possible is currently limited. In this study, we attempted to establish an efficient method for the integrated analysis of glioma-related genes by in vitro amplification of cerebrospinal fluid-derived ccfDNA from glioma patients and a highly sensitive assay.

METHODS

Tumor-derived ccfDNA was extracted and purified from 1 ml of cerebrospinal fluid obtained by lumbar puncture using the Maxwell RSC instrument in five glioma cases. Hot spots of mutations in IDH1 and H3F3A genes were analyzed by high resolution melting (HRM), TERT mutation by droplet digital PCR, MGMT promoter methylation by methylation-specific HRM, and chromosome 1p/19q loss by multiplex ligation-dependent probe amplification. For samples in which the amount of ccfDNA was too small to analyze, DNA was amplified approximately 500-fold by DNA polymerase using the GenomiPhi kit and analyzed by the same assay method.

RESULTS AND CONCLUSIONS

Although two of the five cases required amplification with the GenomiPhi kit, it was possible to analyze all cases for glioma-related genes as described above. Although the amount of ccfDNA obtained from low-grade gliomas and gliomas that are not in contact with the ventricles or subarachnoid space is small, this amplification method may increase the possibility of liquid biopsy using cerebrospinal fluid.
BIOM-37. EVALUATION OF TEMPORALIS MUSCLE THICKNESS WITH TOXICITY AND SURVIVAL IN GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION
Authors: Saraf Anurag , Hill Cameron , Youssef Gilbert , Christ Sebastian , Tanguturi Shyam , McFaline-Figueroa J Ricardo , Chukwueke Ugonma , Lee Eudocia , Reardon David A , Arnaout Omar , Bi Wenya Linda , Haas-Kogan Daphne , Ligon Keith , Alexander Brian , Wen Patrick Y , Rahman Rifaquat
Published: November 2022

BACKGROUND

Treatment-related toxicity is common in patients with glioblastoma (GBM) receiving chemotherapy and radiotherapy (RT). Temporalis muscle thickness (TMT) is a biomarker associated with sarcopenia and worse clinical outcomes in GBM, however its relation to treatment toxicity is less studied. We hypothesize that TMT may predict toxicity and survival in GBM patients.

METHODS

We reviewed consecutive patients with IDH-wildtype GBM treated from 2014-2019 at a single academic center. TMT was retrospectively assessed on T1-weighted MRI scans and dichotomized based upon previously validated sex-specific cutoff values. TMT was measured on baseline MRI scan at time of diagnosis. Cox regression multivariable analysis (MVA) was used to assess survival.

RESULTS

We evaluated 351 patients with median age of 60y (range 20-94) and median follow-up of 14mo. Most patients were male (59%), baseline KPS >70 (95%), and MGMT unmethylated (55%). After maximal safe resection, most patients received standard (90%) or hypofractionated (10%) RT with concurrent systemic therapy (89%). On MVA, baseline low TMT (HR 1.93, p=0.01), age >65y, baseline KPS, and MGMT-unmethylated status were associated with worse OS. On MVA, baseline low TMT (HR 1.95, p=0.01), age >65y, MGMT-unmethylated status, and discontinuing systemic therapy were associated with worse profession-free survival (PFS). 21 patients did not complete anticipated treatment course of chemoradiation and adjuvant systemic therapy due to toxicity, primarily thrombocytopenia, associated with worse OS on MVA (HR 1.99, p< 0.01). Low TMT was associated with higher risk of stopping treatment due to adverse events (OR 5.25, p< 0.01) independent of age, sex, extent of resection, RT dose on MVA.

CONCLUSION

Baseline low TMT was associated with worse PFS and OS, and it was associated with treatment interruption due to treatment toxicity in GBM patients. While further validation is needed, TMT may help identify patients who will benefit from aggressive symptom management or treatment deintensification.
BIOM-42. A DEEP LEARNING MODEL FOR AUTOMATED DETECTION AND COUNTING OF TUNNELING NANOTUBES AND CANCER CELLS IN MICROSCOPY IMAGES
Authors: Ceran Yasin , Ergüder Hamza , Ladner Katherine , Korenfeld Sophie , Deniz Karina , Padmanabhan Sanyukta , Baday Murat , Pengo Thomas , Lou Emil , Patel Chirag
Published: November 2022

BACKGROUND

Tunneling nanotubes (TNTs) are cellular structures connecting cell membranes and mediating intercellular communication. TNTs are manually identified and counted by a trained investigator; however, this process is time-intensive. We therefore sought to develop an automated approach for quantitative analysis of TNTs.

METHODS

We used the convolutional neural network (U-Net) deep learning model to segment phase contrast microscopy images of both cancer and non-cancer cells. Our method was composed of preprocessing and model development. We developed a new preprocessing method to label TNTs on a pixel-wise basis. Two sequential models were employed to detect TNTs. First, we identified the regions of images with TNTs by implementing a classification algorithm. Second, we fed parts of the image classified as TNT-containing into a modified U-Net model to estimate TNTs on a pixel-wise basis.

RESULTS

The U-Net model detected 73.3% of human expert-identified TNTs, counted TNTs and cells, and calculated the TNT-to-cell ratio (TCR). We obtained a precision of 0.88, recall of 0.67, and f-1 score of 0.76 on a test data set. The predicted and true TCRs were not significantly different between the training and test data sets.

CONCLUSIONS

In summary, we report application of an automated model generated by deep learning and trained to accurately label and detect TNTs and cells imaged in culture. Continued application and refinement of this process will provide a new approach to the analysis of TNTs, which form to connect cancer and other cells. This approach has the potential to enhance the drug screens intended to assess therapeutic efficacy of experimental agents, and to reproducibly assess TNTs as a potential biomarker of response to therapy in cancer.