bluuebunny/crossref_metadata_2025 huggingface dataset:
An exploration of the binding prediction of anatoxin-a and atropine to acetylcholinesterase enzyme using multi-level computer simulations
Authors: Mir Showkat Ahmad , Razzokov Jamoliddin , Mukherjee Vishwajeet , Baitharu Iswar , Nayak Binata
Published: November 2023

Acetylcholinesterase (AChE) is crucial for the breakdown of acetylcholine to acetate and choline, while the inhibition of AChE by anatoxin-a (ATX-a) results in severe health complications. This study explores the structural characteristics of ATX-a and its interactions with AChE, comparing to the reference molecule atropine for binding mechanisms. Molecular docking simulations reveal strong binding affinity of both ATX-a and atropine to AChE, interacting effectively with specific amino acids in the binding site as potential inhibitors. Quantitative assessment using the MM-PBSA method demonstrates a significantly negative binding free energy of −81.659 kJ mol−1 for ATX-a, indicating robust binding, while atropine exhibits a stronger binding affinity with a free energy of −127.565 kJ mol−1. Umbrella sampling calculates the ΔG
bind values to evaluate binding free energies, showing a favorable ΔG
bind of −36.432 kJ mol−1 for ATX-a and a slightly lower value of −30.12 kJ mol−1 for atropine. This study reveals the dual functionality of ATX-a, acting as both a nicotinic acetylcholine receptor agonist and an AChE inhibitor. Remarkably, stable complexes form between ATX-a and atropine with AChE at its active site, exhibiting remarkable binding free energies. These findings provide valuable insights into the potential use of ATX-a and atropine as promising candidates for modulating AChE activity.
US crop yield losses from hydroclimatic hazards
Authors: Choi Eunkyoung , Rigden Angela J , Tangdamrongsub Natthachet , Jasinski Michael F , Mueller Nathaniel D
Published: November 2023

Hydroclimatic stresses can negatively impact crop production via water deficits (low soil water supply and high atmospheric demand) or surpluses (high soil water supply and low atmospheric demand). However, the impact of both stresses on crop yields at regional scales is not well understood. Here we quantified yield sensitivities and corresponding spatio-temporal yield losses of US rainfed maize, soybeans, sorghum, and spring wheat to hydroclimatic stresses by considering the joint impacts of root-zone soil moisture and atmospheric evaporative demand from 1981 to 2020. We show that crop yields can be reduced similarly by two major hydroclimatic hazards, which are defined as the most yield damaging conditions over time: ‘Low Supply + High Demand’ and ‘High Supply + Low Demand’. However, more exposure to ‘Low Supply + High Demand’ hazard led to the largest annual yield losses (7%–17%) across all four crops over time. Modeled yield losses due to these hazards were significantly associated with crop insurance lost costs. The extent of yield losses varies considerably by crop and location, highlighting the need for crop-specific and regionally tailored adaptation strategies.
Plasma nitrogen fixation system with dual-loop enhancement for improved energy efficiency and its efficacy for lettuce cultivation
Authors: HAN 韩 Zeyang 泽阳 , ZHANG 张 Mengxue 梦雪 , ZHANG 张 Di 頔 , HE 何 Xin 欣 , JING 井 Tianjun 天军 , GE 葛 Zhixuan 知轩 , LI 李 Yuge 玉鸽 , ZHU 朱 Tong 童 , REN 任 Yunhong 云鸿 , ZHONG 仲 Chongshan 崇山 , JI 季 Fang 方
Published: November 2023

Plasma nitrogen fixation (PNF) has been emerging as a promising technology for greenhouse gas-free and renewable energy-based agriculture. Yet, most PNF studies seldom address practical application-specific issues. In this work, we present the development of a compact and automatic PNF system for on-site agricultural applications. The system utilized a gliding-arc discharge as the plasma source and employed a dual-loop design to generate

from air and water under atmospheric conditions. Experimental results showed that the system with a dual-loop design performs well in terms of energy costs and production rates. Optimal operational parameters for the system were determined through experimentation, resulting in an energy cost of 13.9 MJ mol−1 and an energy efficiency of 16 g kWh−1 for

production, respectively. Moreover, the concentration of exhausted NO
x
was below the emission standards. Soilless lettuce cultivation experiments demonstrated that

produced by the PNF system could serve as liquid nitrate nitrogen fertilizer. Overall, our work demonstrates the potential of the developed PNF system for on-site application in the production of green-leaf vegetables.
Colour vision deficiency in teaching dermatology
Authors: Salava Alexander , Hoffström Jaakko
Published: November 2023

The role of colour vision deficiency is rarely discussed in dermatology education. The authors present some of their own experiences and useful modifications, which have enabled them to improve teaching outcomes.
Sleep apnoea syndrome prevalence in chronic kidney disease and end-stage kidney disease patients: a systematic review and meta-analysis
Authors: Pisano Anna , Zoccali Carmine , Bolignano Davide , D'Arrigo Graziella , Mallamaci Francesca
Published: November 2023

Background

Several studies have examined the frequency of sleep apnoea (SA) in patients with chronic kidney disease (CKD), reporting different prevalence rates. Our systematic review and meta-analysis aimed to define the clinical penetrance of SA in CKD and end-stage kidney disease (ESKD) patients.

Methods

Ovid-MEDLINE and PubMed databases were explored up to 5 June 2023 to identify studies providing SA prevalence in CKD and ESKD patients assessed by different diagnostic methods, either sleep questionnaires or respiration monitoring equipment [such as polysomnography (PSG), type III portable monitors or other diagnostic tools]. Single-study data were pooled using the random-effects model. The Chi2 and Cochrane-I2 tests were used to assess the presence of heterogeneity, which was explored performing sensitivity and/or subgroup analyses.

Results

A cumulative analysis from 32 single-study data revealed a prevalence of SA of 57% [95% confidence interval (CI) 42%–71%] in the CKD population, whereas a prevalence of 49% (95% CI 47%–52%) was found pooling data from 91 studies in ESKD individuals. The prevalence of SA using instrumental sleep monitoring devices, including classical PSG and type III portable sleep monitors, was 62% (95% CI 52%–72%) and 56% (95% CI 42%–69%) in CKD and ESKD populations, respectively. Sleep questionnaires revealed a prevalence of 33% (95% CI 16%–49%) and 39% (95% CI 30%–49%).

Conclusions

SA is commonly seen in both non-dialysis CKD and ESKD patients. Sleep-related questionnaires underestimated the presence of SA in this population. This emphasizes the need to use objective diagnostic tools to identify such a syndrome in kidney disease.
Functional mapping to reveal slow conduction and substrate progression in atrial fibrillation
Authors: Silva Garcia Etel , Lobo-Torres Ivan , Fernández-Armenta Juan , Penela Diego , Fernandez-Garcia Marcos , Gomez-Lopez Andrea , Soto-Iglesias David , Fernández-Rivero Rafael , Vazquez-Garcia Rafael , Acosta Juan , Bisbal Felipe , Cano-Calabria Lucas , Berruezo Antonio
Published: November 2023

Aims

The aim of our study was to analyse the response to short-coupled atrial extrastimuli to identify areas of hidden slow conduction (HSC) and their relationship with the atrial fibrillation (AF) phenotype.

Methods and results

Twenty consecutive patients with paroxysmal AF and persistent AF (10:10) underwent the first pulmonary vein isolation procedure. Triple short-coupled extrastimuli were delivered in sinus rhythm (SR), and the evoked response was analysed: sites exhibiting double or highly fragmented electrograms (EGM) were defined as positive for HSC (HSC+). The delta of the duration of the bipolar EGM was analysed, and bipolar EGM duration maps were built. High-density maps were acquired using a multipolar catheter during AF, SR, and paced rhythm. Spatial co-localization of HSC+ and complex fractionated atrial EGMs (CFAE) during AF was evaluated. Persistent AF showed a higher number and percentage of HSC+ than paroxysmal AF (13.9% vs. 3.3%, P < 0.001). The delta of EGM duration was 53 ± 22 ms for HSC+ compared with 13 ± 11 (10) ms in sites with negative HSC (HSC−) (P < 0.001). The number and density of HSC+ were lower than CFAE during AF (19 vs. 56 per map, P < 0.001). The reproducibility and distribution of HSC+ in repeated maps were superior to CFAE (P = 0.19 vs. P < 0.001). Sites with negative and positive responses showed a similar bipolar voltage in the preceding sinus beat (1.65 ± 1.34 and 1.48 ± 1.47 mV, P = 0.12).

Conclusion

Functional mapping identifies more discrete and reproducible abnormal substrates than mapping during AF. The HSC+ sites in response to triple extrastimuli are more frequent in persistent AF than in paroxysmal AF.
“Everyone’s struggling right now”: Impact of COVID-19 on addressing food insecurity in rural primary care
Authors: Suresh Arvind , Jordanova Kayla E , Boardman Maureen B , Canavan Chelsey R , D’cruze Tiffany T , Dev Alka , Kennedy Meaghan A
Published: November 2023

Background

Primary care practices can address food insecurity (FI) through routine screening, practice-based food programmes, and referrals to community resources. The COVID-19 pandemic had disproportionate impacts on health outcomes for food-insecure households.

Objective

To describe the impact of the COVID-19 pandemic on FI screening and interventions in rural primary care practices in northern New England.

Methods

We conducted semi-structured interviews with thirteen providers and staff regarding changes to FI screening and interventions, community resources and partnerships, and patient food needs during the pandemic. Themes and exemplar quotations were identified through iterative discussion.

Results

Practices reported more frequent informal discussions with patients about FI during the pandemic. Despite limitations in site operations, practices created programmes to distribute food at practice locations or through food deliveries. The adoption of telemedicine had variable impacts on FI screening, creating challenges for some while facilitating screening outside of scheduled visits for others. Practices reported increased food availability due to new or expanded community programmes, but lack of transportation and delivery availability were challenges. New and stronger connections formed between practices and community partners. Increased awareness of FI among both patients and practice staff resulted in decreased stigma.

Conclusion

Screening for and addressing FI was a priority for rural primary care practices during the pandemic. The implementation of practice-based FI interventions was supported by stronger practice-community connections and a decrease in stigma. The experiences of providers and staff during the pandemic provide insight into best practices for engaging primary care practices in reducing FI.
Transcript Isoform Diversity of Ampliconic Genes on the Y Chromosome of Great Apes
Authors: Tomaszkiewicz Marta , Sahlin Kristoffer , Medvedev Paul , Makova Kateryna D
Published: November 2023

Y chromosomal ampliconic genes (YAGs) are important for male fertility, as they encode proteins functioning in spermatogenesis. The variation in copy number and expression levels of these multicopy gene families has been studied in great apes; however, the diversity of splicing variants remains unexplored. Here, we deciphered the sequences of polyadenylated transcripts of all nine YAG families (BPY2, CDY, DAZ, HSFY, PRY, RBMY, TSPY, VCY, and XKRY) from testis samples of six great ape species (human, chimpanzee, bonobo, gorilla, Bornean orangutan, and Sumatran orangutan). To achieve this, we enriched YAG transcripts with capture probe hybridization and sequenced them with long (Pacific Biosciences) reads. Our analysis of this data set resulted in several findings. First, we observed evolutionarily conserved alternative splicing patterns for most YAG families except for BPY2 and PRY. Second, our results suggest that BPY2 transcripts and proteins originate from separate genomic regions in bonobo versus human, which is possibly facilitated by acquiring new promoters. Third, our analysis indicates that the PRY gene family, having the highest representation of noncoding transcripts, has been undergoing pseudogenization. Fourth, we have not detected signatures of selection in the five YAG families shared among great apes, even though we identified many species-specific protein-coding transcripts. Fifth, we predicted consensus disorder regions across most gene families and species, which could be used for future investigations of male infertility. Overall, our work illuminates the YAG isoform landscape and provides a genomic resource for future functional studies focusing on infertility phenotypes in humans and critically endangered great apes.
Reusable glycan microarrays using a microwave assisted wet-erase (MAWE) process
Authors: Mehta Akul Y , Tilton Catherine A , Muerner Lukas , von Gunten Stephan , Heimburg-Molinaro Jamie , Cummings Richard D
Published: November 2023

Modern studies on binding of proteins to glycans commonly involve the use of synthetic glycans and their derivatives in which a small amount of the material is covalently printed onto a functionalized slide in a glycan microarray format. While incredibly useful to explore binding interactions with many types of samples, the common techniques involve drying the slides, which leads to irreversible association of the protein to the spots on slides to which they bound, thus limiting a microarray to a single use. We have developed a new technique which we term Microwave Assisted Wet-Erase (MAWE) glycan microarrays. In this approach we image the slides under wet conditions to acquire the data, after which the slides are cleaned of binding proteins by treatment with a denaturing SDS solution along with microwave treatment. Slides cleaned in this way can be reused multiple times, and an example here shows the reuse of a single array 15 times. We also demonstrate that this method can be used for a single-array per slide or multi-array per slide platforms. Importantly, the results obtained using this technique for a variety of lectins sequentially applied to a single array, are concordant to those obtained via the classical dry approaches on multiple slides. We also demonstrate that MAWE can be used for different types of samples, such as serum for antibody binding, and whole cells, such as yeast. This technique will greatly conserve precious glycans and prolong the use of existing and new glycan microarrays.
Criteria for the procedural fairness of health financing decisions: a scoping review
Authors: Dale Elina , Peacocke Elizabeth F , Movik Espen , Voorhoeve Alex , Ottersen Trygve , Kurowski Christoph , Evans David B , Norheim Ole Frithjof , Gopinathan Unni
Published: November 2023

Due to constraints on institutional capacity and financial resources, the road to universal health coverage (UHC) involves difficult policy choices. To assist with these choices, scholars and policy makers have done extensive work on criteria to assess the substantive fairness of health financing policies: their impact on the distribution of rights, duties, benefits and burdens on the path towards UHC. However, less attention has been paid to the procedural fairness of health financing decisions. The Accountability for Reasonableness Framework (A4R), which is widely applied to assess procedural fairness, has primarily been used in priority-setting for purchasing decisions, with revenue mobilization and pooling receiving limited attention. Furthermore, the sufficiency of the A4R framework’s four criteria (publicity, relevance, revisions and appeals, and enforcement) has been questioned. Moreover, research in political theory and public administration (including deliberative democracy), public finance, environmental management, psychology, and health financing has examined the key features of procedural fairness, but these insights have not been synthesized into a comprehensive set of criteria for fair decision-making processes in health financing. A systematic study of how these criteria have been applied in decision-making situations related to health financing and in other areas is also lacking. This paper addresses these gaps through a scoping review. It argues that the literature across many disciplines can be synthesized into 10 core criteria with common philosophical foundations. These go beyond A4R and encompass equality, impartiality, consistency over time, reason-giving, transparency, accuracy of information, participation, inclusiveness, revisability and enforcement. These criteria can be used to evaluate and guide decision-making processes for financing UHC across different country income levels and health financing arrangements. The review also presents examples of how these criteria have been applied to decisions in health financing and other sectors.
Polar Stars: Toward an Epistemological Understanding of Security Constellations and the Arctic Case
Authors: Fakhoury Renato
Published: November 2023

The reemergence of great power competition, seen most significantly in the tension over Taiwan between the People’s Republic of China and the United States and in the Russian invasion of Ukraine, has sparked interest in the Arctic literature on whether and how great power competition might be emerging in the region. State-centric frameworks have emerged as the primary analytical frameworks within this burgeoning literature. While they offer important insights, the dynamics of security in the region make state-based appraisals limited. Because the Arctic region is a frontier, normative structures upon which state-centric paradigms are predicated—such as state sovereignty—hold less sway than in more traditional arenas of great power competition. As a result, a range of subnational and supranational actors and organizations play a more significant role in terms of security processes and outcomes. Thus, a more comprehensive model of security analysis is needed to understand the drivers of security in the Artic region. To that end, in this article, I analyze the main securitizing moves in the Arctic region, arguing that they incorporate different levels of analysis and present broad degrees of comprehensiveness. I turn to security constellation theory, hitherto a relatively underdeveloped approach that nonetheless offers the potential to accommodate the multifaceted security dynamics of the region.
Characterization of exogenous lactate addition on the growth, photosynthetic performance, and biochemical composition of four bait microalgae strains
Authors: Duan Jiawen , Li Chenhui , Zheng Yimeng , Huang Aiyou , Xie Zhenyu
Published: November 2023

Aims

To quickly obtain the biomass of bait microalgae with high value-added products, researchers have examined the influence of biochemical and environmental factors on the growth rates and biochemical composition of microalgae. Previous studies have shown that lactate plays an important role in metabolic regulation in Phaeodactylum tricornutum. In this study, we investigated the effect of exogenous lactate on the growth rates, photosynthetic efficiency, and biochemical composition of four commonly used bait microalgae in aquaculture.

Methods and results

The optical density of the algal cultures at specific time points, YII, Fv/Fm, and the total lipid, protein, soluble sugar, insoluble sugar, chlorophyll a, and carotenoid content of P. tricornutum, Isochrysis galbana (I. galbana), Chaetoceros muelleri, and Cylindrotheca fusiformis were determined. In I. galbana, the growth rate was enhanced with the addition of lactate, even though higher concentrations of lactate were associated with a decrease in YII and Fv/Fm. In general, the total lipid content of these microalgal strains increased gradually in a concentration-dependent manner over the range of lactate concentrations. In addition, higher concentrations of lactate also induced significant changes in the total soluble and insoluble sugar levels in all microalgal strains. However, chlorophyll a and carotenoid contents increased at lower but decreased at higher concentrations of lactate in all microalgal strains. The total protein content was significantly elevated at all concentrations of lactate in P. tricornutum, whereas there were no significant differences in that of C. fusiformis.

Conclusions

Lactate effective influences in the growth, metabolism, and synthesis of important biochemical components in the four microalgal strains under investigation.
Philosophical silences: race, gender, disability, and philosophical practice
Authors: Wilson Robert A
Published: November 2023

Who is recognized as a philosopher and what counts as philosophy influence both the content of a philosophical education and academic philosophy’s continuing demographic skew. The ‘philosophical who’ and the ‘philosophical what’ themselves are a partial function of matters that have been passed over in collective silence, even if that now feels to some like a silence belonging to the distant past. This paper discusses some philosophical silences regarding race, gender, and disability in the context of reflection on philosophical education and on philosophical practice in the public sphere. It focusses on Charles Mills’ writings on race, Susan Babbitt’s on race and gender, and on more collaboratively generated work on eugenics and disability.
Dectin-2 is critical for phagocyte function and resistance to Paracoccidioides brasiliensis in mice
Authors: Cardoso-Miguel Mariana de Resende Damas , Bürgel Pedro Henrique , de Castro Raffael Júnio Araújo , Marina Clara Luna , de Oliveira Stephan Alberto , Albuquerque Patrícia , Silva-Pereira Ildinete , Bocca Anamélia Lorenzetti , Tavares Aldo Henrique
Published: November 2023

Germline-encoded pattern recognition receptors, particularly C-type lectin receptors (CLRs), are essential for phagocytes to sense invading fungal cells. Among CLRs, Dectin-2 (encoded by Clec4n) plays a critical role in the antifungal immune response as it recognizes high-mannose polysaccharides on the fungal cell wall, triggering phagocyte functional activities and ultimately determining adaptive responses. Here, we assessed the role of Dectin-2 on the course of primary Paracoccidioides brasiliensis systemic infection in mice with Dectin-2-targeted deletion. Paracoccidioides brasiliensis constitutes the principal etiologic agent of paracoccidioidomycosis, the most prominent invasive mycosis in Latin American countries. The deficiency of Dectin-2 resulted in shortened survival rates, high lung fungal burden, and increased lung pathology in mice infected with P. brasiliensis. Consistently, dendritic cells (DCs) from mice lacking Dectin-2 infected ex vivo with P. brasiliensis showed impaired secretion of several proinflammatory and regulatory cytokines, including TNF-α, IL-1β, IL-6, and IL-10. Additionally, when cocultured with splenic lymphocytes, DCs were less efficient in promoting a type 1 cytokine pattern secretion (i.e., IFN-γ). In macrophages, Dectin-2-mediated signaling was required to ensure phagocytosis and fungicidal activity associated with nitric oxide production. Overall, Dectin-2-mediated signaling is critical to promote host protection against P. brasiliensis infection, and its exploitation might lead to the development of new vaccines and immunotherapeutic approaches.
In-plane tidal disruption of stars in discs of active galactic nuclei
Authors: Ryu Taeho , McKernan Barry , Ford K E Saavik , Cantiello Matteo , Graham Matthew , Stern Daniel , Leigh Nathan W C
Published: November 2023

Stars embedded in active galactic nucleus (AGN) discs or captured by them may scatter onto the supermassive black hole (SMBH), leading to a tidal disruption event (TDE). Using the moving-mesh hydrodynamics simulations with arepo, we investigate the dependence of debris properties in in-plane TDEs in AGN discs on the disc density and the orientation of stellar orbits relative to the disc gas (pro- and retro-grade). Key findings are: (1) Debris experiences continuous perturbations from the disc gas, which can result in significant and continuous changes in debris energy and angular momentum compared to ‘naked’ TDEs. (2) Above a critical density of a disc around an SMBH with mass M• [ρcrit ∼ 10−8 g cm−3 (M•/106 M⊙)−2.5] for retrograde stars, both bound and unbound debris is fully mixed into the disc. The density threshold for no bound debris return, inhibiting the accretion component of TDEs, is $\rho _{\rm crit,bound} \sim 10^{-9}{\rm g~cm^{-3}}(M_{\bullet }/10^{6}\, {\rm M}_{\odot })^{-2.5}$. (3) Observationally, AGN-TDEs transition from resembling naked TDEs in the limit of ρdisc ≲ 10−2ρcrit,bound to fully muffled TDEs with associated inner disc state changes at ρdisc ≳ ρcrit,bound, with a superposition of AGN + TDE in between. Stellar or remnant passages themselves can significantly perturb the inner disc. This can lead to an immediate X-ray signature and optically detectable inner disc state changes, potentially contributing to the changing-look AGN phenomenon. (4) Debris mixing can enrich the average disc metallicity over time if the star’s metallicity exceeds that of the disc gas. We point out that signatures of AGN-TDEs may be found in large AGN surveys.
The first fireworks: A roadmap to Population III stars during the epoch of reionization through pair-instability supernovae
Authors: Venditti Alessandra , Bromm Volker , Finkelstein Steven L , Graziani Luca , Schneider Raffaella
Published: November 2023

With the launch of JWST and other scheduled missions aimed at probing the distant universe, we are entering a new promising era for high-z astronomy. One of our main goals is the detection of the first population of stars (Population III or Pop III stars), and models suggest that Pop III star formation is allowed well into the Epoch of Reionization (EoR), rendering this an attainable achievement. In this paper, we focus on our chance of detecting massive Pop IIIs at the moment of their death as Pair-Instability Supernovae (PISNe). We estimate the probability of discovering PISNe during the EoR in galaxies with different stellar masses (7.5 ≤ Log(M⋆/M⊙) ≤ 10.5) from six dustyGadget simulations of 50 h−1 cMpc per side. We further assess the expected number of PISNe in surveys with JWST/NIRCam and Roman/WFI. On average, less than one PISN is expected in all examined JWST fields at z ≃ 8 with Δz = 1, and O(1) PISN may be found in a ∼1 deg2 Roman field in the best-case scenario, although different assumptions on the Pop III IMF and/or Pop III star formation efficiency can decrease this number substantially. Including the contribution from unresolved low-mass haloes holds the potential for increased discoveries. JWST/NIRCam and Roman/WFI allow the detection of massive-progenitor (∼250 M⊙) PISNe throughout all the optimal F200W-F356W, F277W-F444W, and F158-F213 colours. PISNe are also pre-dominantly located at the outskirts of their hosting haloes, facilitating the disentangling of underlying stellar emission thanks to the spatial-resolution capabilities of the instruments.
Cosmology from large populations of galaxy–galaxy strong gravitational lenses
Authors: Li Tian , Collett Thomas E , Krawczyk Coleman M , Enzi Wolfgang
Published: November 2023

We present a forecast analysis on the feasibility of measuring the cosmological parameters with a large number of galaxy–galaxy scale strong gravitational lensing systems. Future wide-area surveys like Euclid and 4MOST are expected to discover and measure the properties of more than 10 000 strong lensing systems. We develop a hierarchical model that can simultaneously constrain the lens population and cosmological parameters by combining Einstein radius measurements with stellar dynamical mass estimates for every lens. Marginalizing over the lens density profiles and stellar orbital anisotropies, we find that w can be constrained, at 68 per cent confidence, to a precision of 0.11 with 10 000 galaxy–galaxy lens systems, which would be better than any existing single-probe constraint. We test our method on 161 existing lenses from various surveys (LSD, SL2S, SLACS, and S4TM), finding w = −0.96 ± 0.46. We also show how to mitigate against the potential systematic of redshift evolution in the mean lens density profile of the population.
BIOM-14. INCREASED RATIO OF GLUTAMATE TO TOTAL CREATINE IN GLIOBLASTOMA PATIENTS WITH THE POST-OPERATIVE EPILEPSY
Authors: Tanaka Kazuhiro , Hashiguchi Mitsuru , Yamanishi Shunsuke , Nagashima Hiroaki , Sasayama Takashi
Published: November 2023

Epilepsy in glioblastoma patients significantly reduces their quality of life; however, little is known about the association between predicting epilepsy and metabolites in tumors. In this study, we used 3.0-T magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) to quantify metabolite concentrations in patients with varying epilepsy histories. MRS data were quantified with linear combination model (LC-Model) software. From January 2013 to April 2020, fifty-one patients with primary glioblastoma underwent pretreatment 3.0-T MRI/1H-MRS scanning. Twenty-one patients (41%) suffered from epilepsy during the postoperative course, although forty-seven patients (97%) took anti-epileptic drug after surgery. MRS data were compared between groups with and without the post-operative epilepsy. The higher ratios of glutamate (Glu) and glutamate + glutamine (Glx) to total creatine (tCr) in the tumor were significantly associated with epilepsy history (Glu/tCr P < 0.001, Glx/tCr P = 0.004, respectively). The receiver operating characteristic curve analysis showed that a Glu/tCr value of 1.81 was 70% sensitive and 90% specific for the prediction of epilepsy during the postoperative course (area under curve: 0.82). These results suggest that the Glu/tCr ratio in tumors can be a predictive maker for early detection of epileptic seizures after surgery in glioblastoma patients.
BIOM-22. CLINICAL ASSESSMENT OF SIGNALING PATHWAY ACTIVITY IN GLIOMA
Authors: Beccari Sol , Voong Viva , Hervey-Jumper Shawn , Berger Mitchel , Phillips Joanna
Published: November 2023

Despite advances in our understanding of tumor biology, many targeted therapies for diffuse glioma have failed without an understanding of why. Improved patient stratification and assessment of biologic activity in window of opportunity clinical trials will address this failure. The clinically validated, robust biomarkers available, however, are limited. Moreover, evidence-based criteria for biospecimen acquisition are lacking. To address this need we investigated the preanalytic variables that impact the assessment of PI3K/AKT/mTOR and MAPK signaling activity at single cell resolution. To replicate the conditions in window of opportunity clinical trials, tumor tissue from a murine model for glioblastoma (GBM) was utilized and the impact of cold ischemia time (CIT), slide storage duration and temperature on detection of key phospho-proteins was determined. We then validated our findings using human glioma samples acquired in the operating room. To assess the PI3K/AKT/mTOR signaling, phosphorylation of proteins at three nodes of the pathway were investigated. Phosphorylated-PRAS40 (p-PRAS40) is upstream of mTOR and phosphorylated-RPS6 (p-RPS6) and phosphorylated-4EBP1 (p-4EBP1) are downstream of mTOR. Detection of cells expressing p-RPS6 was the most robust with no significant alterations up to 6hrs cold ischemia time (CIT). p-4EBP1 signal was unaltered up to 20min CIT, however, decreased at 2h and 6h (p< 0.001). The detection of p-PRAS40 was variable at 20min and showed a decreased tendency at 2h and 6h. For p-RPS6, p-4EBP1, and p-PRAS40 the assessment of protein intensity per cell was highly variable at all time points analyzed (p< 0.05 at 20min, 2h, and 6h). Thus, for assessment of the PI3K/AKT/mTOR pathway in diffuse glioma using clinical samples, the detection of p-RPS6 is the most stable when time elapsed between sample acquisition and downstream processing (CIT) is long, while p-4EBP1 requires short (≤20 min) delays and p-PRAS40 is more variable.
BIOM-24. PREDICTION OF DISTANT RECURRENCE IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD THERAPY
Authors: Chiranth Shivani , Trip Anouk , Christensen Ib , Grunnet Kirsten , Møller Søren , Hasselbalch Benedikte , Muhic Aida , Lassen Ulrik , Poulsen Hans , Urup Thomas
Published: November 2023

BACKGROUND

Infiltrative growth is a hallmark of glioblastoma (GBM) and is a major factor in therapeutic failure. We aimed to identify clinical and molecular factors associated with distance recurrence in glioblastoma patients treated with standard therapy (radiotherapy with concomitant and adjuvant temozolomide).

METHODS

Two prospective cohorts of consecutive, non-selected GBM patients administered standard therapy as primary treatment between year 2005-2016 (Cohort 1) and 2016-2021 (Cohort 2) at Rigshospitalet, Copenhagen were included. Distant recurrence was defined as a new contrast-enhancing tumor > 2 cm from the gross tumor volume. Clinical and molecular factors were screened for association with time to distant recurrence using univariate Cox regression analysis. The final model was generated employing multivariate analysis.

RESULTS

Cohort 1 and 2 included 628 and 395 patients, respectively. Out of the recurrence pattern evaluable patients, distant recurrence was observed in 117 patients (23%) in Cohort 1 and 73 patients (22%) in Cohort 2. PRELIMINARY

RESULTS

In Cohort 1, multivariate analysis showed that corticosteroid use, age, multifocal disease, ECOG performance status, and degree of tumor resection were not associated (p > 0.10) with distant recurrence. Two factors were independently associated with a higher likelihood of distant recurrence, namely non-methylated promoter of the MGMT gene (HR = 1.93; 95% CI:1.27-2.95; p = 0.002) and positive expression of Epidermal Growth Factor Receptor (EGFR) (HR = 3.70; 95% CI: 1.61-8.33; p = 0.002). In Cohort 2, the EGFR status was not available but the association of non-methylated MGMT with distant recurrence was validated (HR = 2.67; 95% CI: 1.62-4.42; p = 0.0001).

CONCLUSION

Non-methylated MGMT and positive EGFR expression were independent predictors of distant recurrence. Non-methylated MGMT was validated in Cohort 2 and can be used for risk stratification and to enrich clinical trials aiming at improved local or distant tumor control.
BIOM-57. UNRAVELING THE DYSREGULATION OF MIR-17/92 CLUSTER IN AGGRESSIVE PEDIATRIC BRAIN TUMORS: IMPLICATIONS FOR NOVEL THERAPEUTIC STRATEGIES
Authors: Arif Shehbeel , Rathi Komal , Naqvi Ammar , Coyle Anne , Hollawell Madison , Storm Phillip , Resnick Adam , Madsen Peter , Koptyra Mateusz
Published: November 2023

The miR-17/92 cluster, commonly referred to as “OncoMir-1,” is extensively studied in cancer due to its oncogenic role, but it has yet to be fully characterized in pediatric brain tumors. In this study, we conduct a comprehensive investigation involving miRNA profiling of 262 pediatric brain tumors, along with sample-matched data from the Pediatric Brain Tumor Atlas, including WGS, RNA-sequencing, proteomics, and phospho-proteomics data. Through miRNA-based unsupervised clustering, we identified four distinct miRNA signatures that transcend histological boundaries. An aggressive cluster (consisting of Medulloblastoma, ATRT, High-Grade Astrocytic Tumors, and some Ependymomas) exhibited the shortest survival and displayed an enriched network of co-expressed miR-17/92 cluster family members and paralogues, specifically miR-106b/25 and miR-106a/363 (p< 0.001). These tumors exhibited significant upregulation of the MIR17HG gene, which encodes the miR-17/92 cluster of miRNAs (p< 0.001). Further exploration of the upstream regulatory mechanisms of MIR17HG identified n-MYC and E2F1/2/3 significantly upregulated (p< 0.01). Additionally, utilizing sample-matched phospho-proteomics data, we found hyperphosphorylation of RB1, the upstream regulator of E2F, at three sites, providing additional evidence of RB1-E2F regulation upstream of MIR17HG. RB1 hyperphosphorylation and subsequent complete inactivation are mediated by the CDK2/Cyclin E complex, which is inhibited by the tumor suppressor p21. Interestingly, p21 (CDKN1A) gene expression was entirely depleted in the aggressive brain tumors group. In summary, our findings reveal the aberrant upregulation of the oncogenic miR-17/92 cluster in a group of aggressive brain tumors, potentially resulting from inactivating hyperphosphorylation of RB1 caused by p21 loss. This event frees E2F transcription factors and enables transcription of MIR17HG. Additionally, our study highlights E2F1/2/3 and CDK2 as potential therapeutic targets not only for aggressive brain tumors but also for other cancers overexpressing the miR-17/92 cluster. Future research will focus on molecular validation and targeting of the miR-17/92 regulatory pathway using available brain tumor cell line models.
CNSC-24. NEURONAL ACTIVITY PROMOTES GLIOMA PROGRESSION THROUGH INDUCING RNA M6A DEMETHYLATION AND PRONEURAL-TO-MESENCHYMAL TRANSITION IN GLIOMA STEM CELLS
Authors: Guo Xiaofan , Wei Qiu , Li Gang
Published: November 2023

High-grade gliomas are lethal brain cancers whose progression is highly driven by neuronal activity. The glioma stem cell (GSC) subpopulation has been identified in glioblastoma and plays a significant role in the resistance of glioma to conventional therapies as well as cancer recurrence. Activity-regulated release of growth factors and electrical synaptic integration promotes glioma growth; however, it is unclear whether neuronal activity plays a role in the mRNA N6-methyladenosine (m6A) level changes in patient glioma tissue. By using chemogenetics techniques, we enhanced and inhibited neuronal activity in vitro and in vivo, and studied how neuronal activity regulates GSC behaviors. Here, we identified that neuronal activity promotes glioma progression and radioresistance through neuronal exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. We revealed that neuronal activity upregulates critical microRNA expression in NDEs (neuro-derived exosomes) and subsequently induces PMT by activating the STAT3 pathway. Chemogenetically activating cortical neurons increases the growth of GSC xenografts in situ. Conversely, reducing neuronal activity inhibited the GSC xenograft growth. Anti-seizure medication treatment suppresses GSC PMT and sensitizes GSCs to radiotherapy in vitro and in vivo. Together, these findings indicate that exosomes of active neurons can promote glioma progression and radioresistance by inducing GSC PMT via neuro-derived extracellular vesicles
CTIM-12. IMMUNOGENICITY OF AN ADDITIONAL DOSE OF COVID-19 VACCINE IN FULLY VACCINATED PATIENTS WITH GLIOMA TO EVALUATE NEW NATIONAL VACCINATION GUIDELINES - A PROSPECTIVE COHORT STUDY
Authors: Schmidt Teresa , Rohn Hana , Trilling Mirko , Agkatsev Sarina , Oster Christoph , Kleinschnitz Christoph , Sure Ulrich , Stuschke Martin , Scheffler Björn , Kebir Sied , Glas Martin
Published: November 2023

Patients diagnosed with glioma belong to a high-risk group during the COVID-19 pandemic. These patients have a compromised immune function due to the malignancy itself, specific anticancer therapies such as temozolomide and symptom-alleviating corticosteroid treatments. While earlier studies have reported successful seroconversion after SARS-CoV-2 immunization in oncological patients, inclusive of those with glioma, the resulting antibody titers remain markedly inferior compared to the healthy population. The recent modification of COVID-19 vaccine guidelines in Germany advocates an additional annual vaccination for glioma patients. Our prospective cohort study endeavors to delineate the immunogenicity in fully immunized glioma patients through assessment of humoral and adaptive immune response post-administration of the supplementary vaccine dose. In this single-center study, glioma patients undergoing tumor-specific therapy will receive an adjunctive dose of the COVID-19 vaccine in conjunction with the seasonal influenza vaccine. A cohort of 70 glioma patients is planned for inclusion, and a comparative analysis will be conducted against a control group consisting of healthy relatives and healthcare professionals. Blood samples will be procured at two distinct intervals: T1, preceding the extra vaccine administration, and T2, 28 days following vaccination. Immunogenicity will be assessed by quantifying anti-SARS-CoV-2 spike (S) protein and nucleocapsid protein (N) concentrations and T-cell responses ascertained using the ELISPOT assay and flow cytometry. In parallel, a comprehensive evaluation of clinical data relevant to therapeutic interventions and corticosteroid usage will be undertaken. At the time of abstract submission, patient recruitment is in progress. Preliminary immunological and clinical data from this investigation, which seek to appraise immune competence and ascertain the clinical implications of the revised COVID-19 vaccination guidelines in glioma patients, will be presented.
CTNI-67. FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS
Authors: Arakawa Yoshiki , Goldlust Samuel , Colman Howard , Reardon David , Welch Mary , Yamaguchi Shigeru , Butowski Nicholas , Li Jian , Iino Shuichi , Song Gregory , Jackman Aimee , Xie Yuran , Wagle Marie-Claire , Lebedinsky Claudia , Narita Yoshitaka
Published: November 2023

BACKGROUND

Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models.

METHODS

This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥ 1 prior therapy; no treatment options beyond standard of care; KPS ≥ 70.

RESULTS

As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥ 9 months. Dose dependent changes in PK and PD were observed.

CONCLUSIONS

DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.
PATH-53. ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA WITH BEND5-NTRK2 FUSION IN A YOUNG ADULT WITH A HISTORY OF CRANIAL RADIATION FOR CHILDHOOD RHABDOMYOSARCOMA
Authors: Fischer Julie , Gilbert Andrea , Shah Shafqat
Published: November 2023

INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare subset of circumscribed astrocytic glioma. While PXA typically has a favorable prognosis, anaplastic (WHO Grade III) PXA (aPXA) has a poorer prognosis. Molecular analysis of PXA often reveals BRAF mutations or CDKN2A/B homozygous deletions. NTRK fusions have been identified in a few cases of pediatric gliomas including PXA. BEND-5 gene alterations have been rarely reported in CNS tumors such as glioblastoma but have not been previously reported in PXA. Case Presentation The patient is a 24-year-old female with history of nasopharyngeal embryonal rhabdomyosarcoma treated with chemotherapy and radiation at age 3. She was tested for Li-Fraumeni Syndrome and was reportedly negative. One year ago, she presented with visual changes and was found to have an occipital aPXA. She underwent a gross total resection but declined further treatment with radiation. Next-generation sequencing (NGS) identified a BEND5-NTRK2 fusion, and she began treatment with Larotrectinib. Serial MRI scans have shown no evidence of disease recurrence. Discussion Pediatric patients are at increased risk for glioma after radiation which is age- and dose/volume-dependent. Radiation-induced gliomas are typically higher grade, present in atypical sites, and have a poor prognosis. Development of PXA following radiation is rare but has been reported. Our patient was diagnosed with aPXA almost 20 years after initial treatment for rhabdomyosarcoma. Her aPXA exhibited a BEND5-NTRK2 fusion and lacked classical BRAF alterations and CDKN2A/B deletions that are present in de novo cases. A Neuro-Onc Panel did not identify her fusion or include testing for BEND5 alterations. However, an expanded RNA Exome Fusion Panel NGS identified a unique fusion, which opened her up to targeted treatment with an NTRK inhibitor. Our patient is now 1 year from resection without disease progression on larotrectinib. This case highlights the importance of expanded NGS testing, particularly in rare tumors.
NIMG-16. THE PROGNOSTIC VALUE AND BIOLOGICAL SIGNIFICANCE OF MRI CE-T1-BASED RADIOMICS MODELS IN CNS5-IDENTIFIED GBM
Authors: Zhang Mingwei , Wang Xuezhen , Li Xiaoxia , Li Shan , Yue Qiuyuan , Hong Jinsheng
Published: November 2023

BACKGROUND

Following the publication of the 2021 WHO Classification of CNS Tumors (Fifth Edition) (CNS5), prognostic markers to guide the individualized treatment of patients with glioblastoma (GBM) (CNS5) need to be explored. Radiomics is a non-invasive, reproducible, and cost-effective method that has been used in the prognostic assessment of multiple solid tumors. The prognostic value and biological significance of MRI T1 - weighted enhancement (CE-T1) - based radiomics models in GBM (CNS5) has not been reported.

METHODS

The tumor region of MRI CE-T1 phase was segmented, and radiomics features were extracted. The consistency analysis, univariate Cox regression and two machine learning algorithms were used for feature reduction. Then, the radiomics prognostic model was established to calculated the radiomics score (RS). The independent external validation was independently verified using the bicenter radiotherapy cohorts. The enrichment analyses of the differential genes between RS-high and -low groups were implemented to explore the biological significance.

RESULTS

A prognostic model composed of six radiomics features were built. A high RS (HR=3.718, 95%CI: 2.222−6.220, P< 0.001) was an independent risk factor for overall survival (OS). The result was externally validated by two cohorts. Through biological significance exploration, RS was found to be significantly correlated with DNA repair (P=0.009) and glycolysis (P=0.001) pathway enrichment scores. RS was associated with γδT cell infiltration and the expression of LAG3.

CONCLUSION

The MRI CE-T1 based radiomics prognostic models constructed can predict GBM (CNS5) prognosis noninvasively and effectively, which is relevant to DNA repair, and may guide the screening of radiosensitive populations.