bluuebunny/crossref_metadata_2025 huggingface dataset:
Theory
Authors: Dierking Ingo , Martins Figueiredo Neto Antônio
Published: June 2024

In this chapter we will revise some basic aspects of the Onsager and the Landau–de Gennes theories to describe the nematic to isotropic and nematic to nematic phase transitions. These theories are mean-field theories and catch the main physical aspects of these transitions. The topology of the phase diagrams of micellar lyotropic nematic liquid crystals is presented. In particular, the need of a non-critical order parameter is discussed, to account for the presence of the biaxial nematic phase between the two uniaxial phases. It is not our aim here to repeat the mathematical calculations of these theories, since there is a good bibliography about them. In particular, good books can be consulted by readers with detailed descriptions of these theories and extensive bibliography.
A Bayesian convolutional neural network-based generalized linear model
Authors: Jeon Yeseul , Chang Won , Jeong Seonghyun , Han Sanghoon , Park Jaewoo
Published: June 2024

Convolutional neural networks (CNNs) provide flexible function approximations for a wide variety of applications when the input variables are in the form of images or spatial data. Although CNNs often outperform traditional statistical models in prediction accuracy, statistical inference, such as estimating the effects of covariates and quantifying the prediction uncertainty, is not trivial due to the highly complicated model structure and overparameterization. To address this challenge, we propose a new Bayesian approach by embedding CNNs within the generalized linear models (GLMs) framework. We use extracted nodes from the last hidden layer of CNN with Monte Carlo (MC) dropout as informative covariates in GLM. This improves accuracy in prediction and regression coefficient inference, allowing for the interpretation of coefficients and uncertainty quantification. By fitting ensemble GLMs across multiple realizations from MC dropout, we can account for uncertainties in extracting the features. We apply our methods to biological and epidemiological problems, which have both high-dimensional correlated inputs and vector covariates. Specifically, we consider malaria incidence data, brain tumor image data, and fMRI data. By extracting information from correlated inputs, the proposed method can provide an interpretable Bayesian analysis. The algorithm can be broadly applicable to image regressions or correlated data analysis by enabling accurate Bayesian inference quickly.
Digital and technological solutions in cardiovascular nursing and perspectives for a smooth digital shift: a discussion paper
Authors: Conte Gianluca , Magon Arianna , Caruso Rosario
Published: June 2024

Digital and technological solutions (DTS) in cardiovascular nursing are profoundly transforming the landscape of patient care by integrating advanced data-driven approaches. DTS help to enhance patient outcomes and streamline clinical workflows, supporting the shift of the traditional roles of healthcare providers and patients towards more engaged and collaborative care processes. This article presents a perspective in this regard. The adoption of DTS, including mobile health applications and wearable devices, enables continuous monitoring and management of patient health, fostering significant improvements in cardiovascular health management. However, the rapid incorporation of such technologies presents various challenges, such as robust data standardization, the development of digital literacy among healthcare professionals, and addressing privacy and security concerns. Effective integration of DTS into nursing practice demands structured clinical curricula that equip nurses with essential technological skills and a deep understanding of ethical considerations. Theoretical frameworks should guide the systematic implementation and integration of digital tools, ensuring comprehensive consideration of the complexities involved in digital transformations in healthcare.
Making sense of the king’s flight to Varennes
Authors: Escalante Pablo
Published: June 2024

This article attempts to show that at the time of Louis XVI’s flight to Varennes, most people made sense of the event within a horizon of meaning constituted by traditional narratives of kingship. The first section sets out some of the main features of these traditional narratives to show how they framed interpretations of the king’s political behaviour before and after his unsuccessful attempt to reach Montmédy. The second section shows how these traditional narratives of kingship also conditioned interpretations of Louis XVI’s public declarations once he was brought back to Paris. The third section highlights the persistence of public confidence in his person until July 1792. Finally, the fourth section shows how it was only after the abolition of the monarchy that the now dominant narrative of the Varennes episode was fixed as such, as part of a strategy to delegitimize kingship in the public sphere and thus help to stabilize the Republic in France.
The jacktree genome and population genomics provides insights for the mechanisms of the germination obstacle and the conservation of endangered ornamental plants
Authors: Zhu Sheng , Wei Xue-Fen , Lu Yu-Xin , Zhang Dao-Wu , Wang Ze-Fu , Ge Jing , Li Sheng-Lian , Song Yan-Feng , Yang Yong , Yi Xian-Gui , Zhang Min , Xue Jia-Yu , Duan Yi-Fan
Published: June 2024

Sinojackia Hu represents the first woody genus described by Chinese botanists, with all species classified as endangered ornamental plants endemic to China. Their characteristic spindle-shaped fruits confer high ornamental value to the plants, making them favored in gardens and parks. Nevertheless, the fruits likely pose a germination obstacle, contributing to the endangered status of this lineage. Here we report the chromosome-scale genome of S. xylocarpa, and explore the mechanisms underlying its endangered status, as well as its population dynamics throughout evolution. Population genomic analysis has indicated that S. xylocarpa experienced a bottleneck effect following the recent glacial period, leading to a continuous population reduction. Examination of the pericarp composition across six stages of fruit development revealed a consistent increase in the accumulation of lignin and fiber content, responsible for the sturdiness of mature fruits’ pericarps. At molecular level, enhanced gene expression in the biosynthesis of lignin, cellulose and hemicellulose was detected in pericarps. Therefore, we conclude that the highly lignified and fibrotic pericarps of S. xylocarpa, which inhibit its seed germination, should be its threatening mechanism, thus proposing corresponding strategies for improved conservation and restoration. This study serves as a seminal contribution to conservation biology, offering valuable insights for the study of other endangered ornamental plants.
The Aut Dedere Aut Judicare System for Crimes Against Humanity
Authors: Colorio Matteo
Published: June 2024

The aut dedere aut judicare system is critical in the global fight against impunity for the most heinous crimes. Such a system ensures the creation of a widespread web for the elimination of safe havens for perpetrators of these crimes and pursues that goal by empowering and obligating national jurisdictions to discharge their share of the burden in international criminal justice. Indeed, an aut dedere aut judicare system consists of two core elements: an obligation to extradite or prosecute any alleged offender found in the state’s territory and an obligation to establish a title of conditional universal jurisdiction. However, absent a specialized convention, such a system is currently missing for crimes against humanity. To fill this serious gap, the International Law Commission elaborated a proposal for a new convention incorporating a rather satisfactory aut dedere aut judicare system in Draft Articles 7 and 10. The system envisioned by the ILC for crimes against humanity is at the core of the present analysis.
(051) METHAMPHETAMINE-INDUCED VAGINAL LUBRICATION IN RATS AND THE ESTROUS CYCLE
Authors: Mott M , Goeders N
Published: June 2024

Introduction

In an interview-based study performed by our lab of women who use methamphetamine (meth), we previously found that the drug, when delivered intravenously (IV), produces a feeling indistinguishable from an orgasm, which is accompanied by a flushing sensation and the production of excessive vaginal lubrication. We have also reported meth-induced vaginal lubrication in an anesthetized animal model. This production of vaginal transudate was dependent on the dose of meth used and the potent vasodilator nitric oxide.

Objective

The objective of the current study was to assess meth-induced vaginal lubrication across different stages of the estrous cycle and following ovariectomy (ovx) in anesthetized rats, and to assess plasma levels of two signaling molecules associated with sexual arousal.

Methods

Anesthetized rats, each previously implanted with a chronic indwelling jugular catheter, were anesthetized and given one IV infusion of meth (0.24 mg/kg) and vaginal lubrication was measured. A pre-weighed cotton-tipped swab, inserted into the vaginal canal, collected fluid secreted following the administration of meth. Blood was withdrawn before and at ten and fifteen minutes after meth administration either via the jugular catheter or via a small tail snip to measure plasma levels of estradiol and nitric oxide. Testing was completed at each stage of the estrous cycle as well as before and after ovariectomy.

Results

Estradiol and nitric oxide increased following meth infusion similarly across all stages of the estrous cycle. Vaginal lubrication increased more with meth treatment than with saline treatment. This was true across all stages of the estrous cycle and despite ovariectomy.

Conclusions

These findings have far-reaching implications for those who suffer from vaginal dryness. The mechanism underlying this phenomenon may present a novel pharmacotherapeutic target to treat vaginal dryness. Since meth still produced vaginal secretions in anesthetized rats, these results suggest that targeting this mechanism may even prove beneficial in post-menopausal women, a patient group likely at highest risk for experiencing vaginal dryness.

Disclosure

Any of the authors act as a consultant, employee or shareholder of an industry for: Embera Neuurotherapeutics & JanOne.
(130) PREVALENCE OF CONDITIONS INVOLVING ABERRANT MAST CELL ACTIVITY IN PATIENTS WITH NEUROPROLIFERATIVE VESTIBULODYNIA
Authors: Goldstein S W , Kim N N , Drian A , Mueller J , Modena B , Dempsey T , Yee A , Goldstein I
Published: June 2024

Introduction

Neuroproliferative vestibulodynia (NPV) is a provoked vestibular pain shown to be associated with excess immunohistochemical staining for CD117 and PGP9.5, consistent with mast cells and nerves, respectively. NPV is distinguished from control tissue by having >8 mast cells/high power field.

Objective

In patients with a histopathologically confirmed diagnosis of NPV, we wished to assess the prevalence of concomitant conditions involving other aberrant mast cell activity.

Methods

Medical records from people with vulvas who underwent vestibulectomy between June 1, 2019 and October 31, 2023 at a single facility were retrospectively reviewed. All had histopathologically confirmed NPV, having observed > 8 positive CD117 stained cells/high power field in the sub-epithelial stroma. As part of their history, each patient provided a list of medical conditions which included disorders where aberrant mast cell activity has been reported. The following eight conditions were included in medical history forms: asthma, chronic sinusitis, endometriosis, food allergy/intolerance, interstitial cystitis, irritable bowel syndrome, migraine, and postural orthostatic tachycardia syndrome.

Results

A total of 88 NPV patients were included in this chart review. A total of 34 (39%) reported no other aberrant mast cell activity, however 54 (61%) had at least one concomitant condition. The most common conditions were migraine (n=21; 24%), interstitial cystitis (n=17; 19%) and endometriosis (n=15; 17%), followed by food allergy/intolerance (n=12; 14%), irritable bowel syndrome (n=9; 10%), asthma (n=9; 10%), chronic sinusitis (n=5; 6%) and postural orthostatic tachycardia syndrome (n=2; 2%). Among these 88 patients, a total of 33 (38%), 13 (15%), 3 (6%), 1 (1%) and 2 (2%) had one, two, three, four and five other conditions involving aberrant mast cell activity, respectively. There was no correlation between the number of concomitant conditions with aberrant mast cell activity reported and the density of CD117-immunopositive staining in the overall NPV cohort, whether diagnosed with lifelong or acquired NPV.

Conclusions

Patients with histopathologically confirmed NPV have a high prevalence of concomitant conditions associated with aberrant mast cell activity, possibly due to a genetic predisposition. While more studies are needed, NPV is likely part of a broader systemic collection of conditions associated with aberrant mast cell activity. This finding is relevant in terms of future diagnostic and treatment options for patients with NPV.

Disclosure

No.
The Nature of Contemporary African Moral and Political Philosophy: An Introduction
Authors: Lougheed Kirk
Published: June 2024

While there has long been philosophical thinking on the African continent, it was not until the middle of the 20th century that professional philosophy emerged on the continent. Though traditional African cultures have rich oral histories that some contemporary philosophers explicitly draw upon, it was not until universities emerged that there was philosophy conducted by professional philosophers who published their findings in academic venues. To date, much of this work has been conducted in English. The emphasis this tradition places on the community and social harmony will probably stand out immediately to any reader steeped in the Western philosophical tradition. The articles in this issue represent different styles of conducting African philosophy, such as employing analytic methods in order to develop moral theories, questioning the use of Western epistemic standards, and mining ideas from the history of Africa.
Morphological and dietary changes encoded in the genome of Beroe ovata, a ctenophore-eating ctenophore
Authors: Vargas Alexandra M , DeBiasse Melissa B , Dykes Lana L , Edgar Allison , Hayes T Danielle , Groso Daniel J , Babonis Leslie S , Martindale Mark Q , Ryan Joseph F
Published: June 2024

As the sister group to all other animals, ctenophores (comb jellies) are important for understanding the emergence and diversification of numerous animal traits. Efforts to explore the evolutionary processes that promoted diversification within Ctenophora are hindered by undersampling genomic diversity within this clade. To address this gap, we present the sequence, assembly and initial annotation of the genome of Beroe ovata. Beroe possess unique morphology, behavior, ecology and development. Unlike their generalist carnivorous kin, beroid ctenophores feed exclusively on other ctenophores. Accordingly, our analyses revealed a loss of chitinase, an enzyme critical for the digestion of most non-ctenophore prey, but superfluous for ctenophorivores. Broadly, our genomic analysis revealed that extensive gene loss and changes in gene regulation have shaped the unique biology of B. ovata. Despite the gene losses in B. ovata, our phylogenetic analyses on photosensitive opsins and several early developmental regulatory genes show that these genes are conserved in B. ovata. This additional sampling contributes to a more complete reconstruction of the ctenophore ancestor and points to the need for extensive comparisons within this ancient and diverse clade of animals. To promote further exploration of these data, we present BovaDB (http://ryanlab.whitney.ufl.edu/bovadb/), a portal for the B. ovata genome.
ATRT-09. MULTI-OMICS SEQUENCING OF ATYPICAL TERATOID RHABDOID TUMORS UNVEILS A SHARED GROUND-STATE POPULATION PROMOTING SUBGROUP-SPECIFIC DIFFERENTIATION TRAJECTORIES
Authors: Carmona Enrique Blanco , Paassen Irene , He Jiayou , Büllesbach Annette , Buhl Juliane L , Federico Aniello , Liu Ilon , Young Matthew , Kildisiute Gerda , Behjati Sam , Vibhakar Rajeev , Donson Andrew , Foreman Nicholas , Hovestadt Volker , Shaw McKenzie , Chi Susan N , Frühwald Michael , Korshunov Andrey , Hasselblatt Martin , Hoving Eelco W , Jäger Natalie , Johann Pascal D , Pfister Stefan M , Filbin Mariella , Drost Jarno , Kool Marcel
Published: June 2024

BACKGROUND

Atypical teratoid rhabdoid tumors (ATRTs) remain a significant clinical challenge in pediatric neurooncology. Despite the simplicity of the genomic profile, mostly characterized by the functional loss of SMARCB1 and in rare cases SMARCA4, ATRTs are molecularly and epigenetically diverse, with three main molecular subgroups identified: ATRT-TYR, ATRT-SHH and ATRT-MYC.

METHODS

To address the lack of effective mechanism-of-action based treatments and comprehend the biology of these subgroups, we conducted 10X single-nucleus transcriptome (n = 12) and multiome (transcriptome + ATAC) (n = 7) sequencing on tumor samples (ATRT-TYR = 6, ATRT-SHH = 9, ATRT-MYC = 4). Validation datasets included 10X single-cell transcriptomics (n = 1), 10X single-nucleus transcriptomics of cell lines (n = 5), and single-cell (n = 3) and single-nucleus (n = 9) SMART-seq transcriptomics. Separation of malignant cells from tumor microenvironment (TME) cells was achieved by comparison of expression profiles against literature-based marker genesets of normal cell types. Tumor cell populations were characterized based on enrichment in fetal cell types and recurrent tumor programs across cancer types, coupled with non-negative matrix factorization (NMF) and differential expression analyses.

RESULTS

ATRT-TYR exhibited choroid plexus-like and cilia-like cell populations, ATRT-SHH displayed radial glia-like, OPC-like and NPC-like cell populations and ATRT-MYC mainly demonstrated a mesenchymal-like cell population. Each subgroup represented unique differentiation trajectories. However, we identified a population of intermediate neuronal precursor-like cells (IPC-like) shared across all subgroups, expressing markers of pluripotent stem cells and cell cycle. RNA + ATAC transcription factor (TF) enrichment analysis for IPC-like cells revealed TFs linked to each subgroup’s differentiation trajectory, suggesting IPC-like cells as a putative ground-state tumor cell population driving differentiation of each subgroup. Functional validation of these findings in ATRT organoid models is currently ongoing.

CONCLUSIONS

This study elucidates defined ATRT subgroup-specific differentiation trajectories that may provide guidance for the development of subgroup-based therapies.
ATRT-16. MAPPING THE DISORDERED METHYLOME IN ATRT
Authors: Tetens Ashley R , Lunsford Kayleigh E , Liapodimitri Athanasia , Craig-Schwartz Jordyn , Findlay Tyler , Raabe Eric H , Koldobskiy Michael A
Published: June 2024

BACKGROUND

Atypical Teratoid Rhabdoid Tumor (ATRT) is an aggressive pediatric brain tumor driven by inactivation of the chromatin regulator SMARCB1, with remarkably few other mutations. SMARCB1 loss leads to epigenetic dysregulation which plays a pivotal role in ATRT development and progression, and DNA methylation profiling has distinguished molecular subgroups of this disease. However, studies that provide a static view of the epigenome may not capture epigenetic variability that drives cellular plasticity and heterogeneity. Mapping epigenetic variability is crucial to understanding the phenotypic plasticity of this tumor and its ability to evade therapeutic interventions in the clinic.

METHODS

We performed whole genome bisulfite sequencing (WGBS) on 22 ATRT samples, 4 normal fetal brain controls, and 1 hindbrain neural stem cell control, and applied a novel analytic pipeline (InformME) to generate DNA methylation potential energy landscapes encapsulating epigenetic stochasticity. This characterizes mean methylation as well as methylation entropy. We identified key genes and regulatory regions with the most stochastic methylation signatures.

RESULTS

We find that ATRT exhibits a globally destabilized epigenome, with markedly elevated methylation entropy (a measure of variability/disorder). Methylation discordance mapped to key regulatory regions including bivalent promoters, quiescent chromatin regions, and enhancers, and specific genes, with an enrichment for targets of the Polycomb repressive complex 2 and regulators of pluripotency and differentiation.

CONCLUSIONS

The disordered methylome of ATRT could play a critical role in the tumor’s ability to evade therapies. Mapping the targets of epigenetic instability can identify targets for intervention. Moreover, strategies to constrain epigenetic variability may have therapeutic benefit by limiting the number of epigenetic states available to cancer cells.
ATRT-19. CELL SURFACE PROTEOME ANALYSIS OF ATRT IDENTIFIES CD44V6 AS A CAR TARGET
Authors: Cole Allison , Hoffmeyer Eric , Grimaldo Enrique , Donson Andrew , Vibhakar Rajeev , Nellan Anandani , Mitra Siddhartha S
Published: June 2024

Atypical teratoid rhabdoid tumor (ATRT) is an uncommon, aggressive tumor affecting the brain and spinal cord primarily in children. Despite significant strides in understanding cancer biology through DNA and RNA sequencing, nearly 90% of ATRTs exhibit a crucial deletion that triggers rampant tumor growth. The absence of easily targetable genetic mutations in ATRT complicates the development of effective treatments, necessitating innovative strategies for therapy. Evading immune system detection is a key feature of cancer cells. In our study, we conducted an exhaustive, unbiased examination of 350 surface receptors through high-throughput multicolor flow cytometry on samples from ATRT surgeries, cell lines, and xenograft models derived from patients. By using a combination of antibodies targeting CD31, CD45, CD11b, CCR2, Cx3CR1, CD4, and CD8, we could identify immune cell populations within the tumors. Our findings revealed a heightened presence of CD44, CD146, CD59, CD151, and CD276 on the surface. Using qPCR we identified CD44V6 a variant isoform of the CD44 molecule, which is a cell surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration. CD44 has multiple isoforms generated through alternative splicing, with CD44V6 being one of these variants. This specific isoform includes an additional variable exon (exon v6) in its extracellular domain. CD44v6-directed CAR-T cells effectively controlled tumor growth in multiple myeloma and solid tumors such as HNSCC, lung and ovarian adenocarcinomas. We developed CD44V6-directed CAR-T cells and investigated the capacity of Anti-CD44v6 CAR-T cells to execute cytotoxicity against ATRT tumor cells. We see significant cell killing by Anti-CD44v6 CAR-T cells in vitro and a significant increase in the survival of ATRT tumor-bearing mice.
BIOM-04. ALTERED IMMUNE ACTIVATION AND REDUCED LYMPHOPOIESIS IN TREATMENT NAÏVE PEDIATRIC BRAIN TUMOUR PATIENTS
Authors: Baldo Giada Del , Rosichini Marco , Vinci Maria , Carai Andrea , Cacchione Antonella , De Luca Carmen Dolores , Benini Francesca , Genah Shirley , Concetti Marianna , Mastronuzzi Angela , Locatelli Franco , Velardi Enrico
Published: June 2024

Pediatric central nervous system (CNS) tumors are the most common solid tumor in children. Despite improvements in diagnostic and therapeutic approaches over time, treatment effectiveness remains unsatisfactory. Optimal immune function is critical to protect against development and dissemination of cancer and to offer the ideal conditions for the success of anticancer treatment. Here we analyzed the peripheral immunological features of patients affected by pediatric brain tumors, the process of de novo T- and B-cell development and its association with the lymphopenia often observed in these patients. Eighty-six steroids-naïve pediatric patients with CNS tumors at the onset of the disease were included in the study. Brain tumors were classified into low-grade gliomas (LGG: n=44, 51%), pediatric-type diffuse high-grade gliomas (pHGG: n=16, 19%), medulloblastoma (n =9, 10%), and other CNS tumors (n =17, 20%). Patient’s peripheral immunological status was analyzed by flow-cytometry and by evaluating T-cell receptor excision circles (TRECs) and kappa-deleting excision circles (KREC) to quantify T- and B-cell neogenesis. Although all patients showed tendencies towards low lymphocyte counts, this effect was particularly evident in pHGG patients. T-cells of pHGG patients displayed a shift from naïve to effector memory phenotype compared to age-matched controls. On the other hand, LGG patients were characterized by an expansion of the T-central memory pool and higher expression of T-cell activation markers. Both patient cohorts exhibited decreased frequency of B-cells with activated phenotype. Interestingly, pHGG patients exhibited reduced thymic function as revealed by reduced levels of the recent thymic emigrant population and TRECs. In addition, LGG and pHGG patients were characterized by lower KREC values, suggesting suboptimal B-cell formation. At diagnosis, pediatric patients with brain tumor show alterations in their immunological status and reduced thymic and medullary lymphopoiesis, particularly pronounced in pHGG, which may contribute to explain the systemic lymphopenia characterizing these patients.
BIOM-07. DEVELOPING A CEREBROSPINAL FLUID-BASED BIOMARKER FOR MINIMAL RESIDUAL DISEASE AND RELAPSE IN PAEDIATRIC BRAIN TUMOURS USING METABOLOMIC METHODS
Authors: Whitby Alison , Shastri Bhoomi , Kim Dong-Hyun , Dandapani Madhumita
Published: June 2024

BACKGROUND

Many paediatric brain tumours have poor outcomes due to relapse (50% in ependymoma and 30% in medulloblastoma) following treatment. Most of these occur within two years, suggesting persistent minimal residual disease (MRD) below the imaging detection threshold. Diagnosing MRD at the end-of-treatment or early relapse using a sensitive, minimally-invasive liquid biopsy could improve outcomes. Extracting metabolites arising from aberrant cancer metabolism, from cerebrospinal fluid (CSF) is promising because of the proximity of tumour to CSF.

METHODS

Liquid chromatography coupled with tandem high-resolution mass spectrometry (LC-MS/MS) using 25µl CSF extracted with 75µl methanol was shown to differentiate malignant paediatric brain tumours (n=47;day 14 samples) from controls (n=49).

RESULTS

Ependymomas (n=33) differed from medulloblastomas (n=14). Eighteen metabolites were identified as differentially abundant between tumours and controls with 14 metabolites being increased in abundance in tumours. These included amino acids and derivatives (n=8), metabolites in one carbon metabolism (n=1), carnitine cycle (n=2), aerobic glycolysis (n=2), purine catabolism (n=2), ascorbate degradation (n=1) and creatinine synthesis (n=2). From those, betaine/creatinine ratio gave an area under the curve (AUC) of 0.96 (excellent) in receiver operating curve analysis. Using a cut-off ratio of 0.1775 for discriminating brain tumours from controls, had sensitivity and specificity of 92% and 89%. Medulloblastomas were largely similar to ependymomas; nevertheless, three metabolites could discriminate between them, and met the criteria of corrected p<0.05. A ratio of glutarate semialdehyde/malic acid had AUC of 0.85 (good). With a cut-off ratio of 0.0422, the sensitivity and specificity were 79% and 82%.

CONCLUSION

This is the first CSF-based metabolomics study in ependymoma and third in medulloblastoma. Ratios of CSF metabolites can be used as biomarkers to detect brain tumours sensitively and specifically. This work will further be developed into a liquid biopsy test for the detection of MRD and early tumour recurrence.
BIOM-08. CDKN2A --AN INDEPENDENT CYCLIN-DEPENDENT KINASE INHIBITOR VARIANT ASSOCIATED WITH MALIGNANCY AND WITH SMALL VESSEL STROKE, AS A POTENTIAL MARKER FOR RISK OF LARGE-VESSEL STROKE COMPLICATING BENIGN TERATOMA
Authors: Patel Krupesh B , Stapleton Stacie , Smyth Matthew D , Crus-Florez Valerie A , Gonzonlaz-Gomez Ignacio , Luckas Claudia , Geller Thomas J
Published: June 2024

BACKGROUND

Cyclin-dependent kinase inhibitor variants, particularly those of CDKN2A are known to be associated with autosomal dominant Familial Atypical Multiple Mole/Melanoma Syndrome and pancreatic cancer predisposition. These variants are associated with risk of small vessel stroke in African/ African-American populations, and are risk factors for stroke in Nordic populations with hypertension, independent of cardiovascular risk factors.

METHODS

We performed a case review of a female presenting in late infancy with a central nervous system teratoma, that later was complicated by a right hemispheric middle cerebral artery (MCA)stroke, associated with a CDKN2A germline mutation.

RESULTS

This 14month old female presented with transient alterations of consciousness and apparent abdominal migraine events with pernicious vomiting. Neuroimaging revealed a right heterogeneous para- suprasellar mass and bilateral complex arachnoid adjacent cysts. She was observed closely for any progression, as the lesion was immediately adjacent to the optic chiasm. One year after presentation, she developed an acute ischemic right middle cerebral artery (MCA) stroke and had radiographic evidence of severe stenosis and decreased flow primarily within the right supra-clinoid internal carotid artery, the M1 segment and portion of the right A1 segment of cerebral vessels, with decreased enhancement and number of vessels in the distal right MCA territory. The vessels did not appear to be compressed by any mass effect. The radiologic appearance was consistent with vasospasm. The patient upon stoke recovery, underwent near- complete resection of the mass with no evidence of disruption of the capsule surrounding it and no vascular infiltration. Pathology revealed the expected teratoma with prominence of pancreatic acinar structures, and molecular evidence of a variant of CDKN2A, which was present in the patient and mother in the germline.

CONCLUSION

We propose that the imaging evidence of a vasculopathy was related to the genotype at the cyclin- dependent kinase site.
BIOM-12. LIQUID BIOPSIES IN CNS TUMORS: A COMBINED APPROACH TO PROFILING CSF
Authors: Nobre Liana , Nakano Yoshiko , Burns Ian , Johnson Monique , Sheth Javal , Rana Mansuba , Yuditskiy Richard , Negm Logine , Zapotocky Michal , Stucklin Ana , Erker Craig , Cacciotti Chantel , Fleming Adam , Cheng Sylvia , Huang Annie , Bondoc Andrew , Fat MaryJane Lim , Das Anirban , Magimairajan Vanan , Bennet Julie , Siddaway Robert , Tabori Uri , Hawkins Cynthia
Published: June 2024

In precision medicine, molecular profiling of pediatric tumors is crucial for diagnosis, prognosis, and therapeutic decision-making. Traditional biopsy methods, often invasive, have inherent risks and may not capture a tumor’s heterogeneity. Liquid biopsy, however, offers a minimally invasive and comprehensive alternative. We demonstrate its utility in diagnosing and monitoring brain tumors using cell-free DNA (cfDNA) from cerebrospinal fluid (CSF), where conventional cfDNA plasma analysis has shown low sensitivity. Through digital droplet PCR, we analyzed 23 plasma samples from patients with BRAFV600E or H3K27M gliomas, detecting H3K27M in a single case. Conversely, CSF samples revealed 8 positives out of 9 for these mutations, underscoring CSF’s diagnostic value. We advanced our methodology by developing a 21-gene hybrid-capture panel paired with low-pass whole-genome sequencing to pinpoint copy number variations. In our reference sample set, the panel achieved a detection limit with variant allele frequencies as low as 0.5%. With 10ng of cfDNA, we reached 83% sensitivity and 100% specificity, which increased to 100% sensitivity with a 30ng input. Using this assay, we profiled 141 CSF samples from 119 patients, achieving 70% positivity rate in active disease cases in a validation cohort—ranging from 50% in low-grade gliomas to 84% in high-grade gliomas and 75% in medulloblastomas. Intriguingly, of 14 queried tumor samples lacking biopsy confirmation, half showed positive ctDNA results using the panel and/or low-pass whole-genome sequencing. This approach allowed for differential diagnoses in suspected medulloblastoma relapses, tailored therapeutic interventions based on CSF profiles, and effective treatment response monitoring. In summary, our integrated liquid biopsy strategy showcases a powerful, clinically applicable tool that significantly enhances patient care in pediatric neuro-oncology.
BIOM-14. UTILITY OF MIRNA-BASED LIQUID BIOPSY AND RADIOGRAPHIC IMAGING IN PEDIATRIC BRAIN TUMOR PATIENTS
Authors: Arif Shehbeel , Madsen Peter , Familiar Ariana , Rathi Komal , Coyle Anne , Foster Jessica , Naqvi Ammar , Nabavizadeh Ali , Storm Phillip B , Hollawell Madison , Koptyra Mateusz , Resnick Adam C
Published: June 2024

BACKGROUND

MRI is the current gold standard imaging technique for diagnostic evaluation and monitoring of pediatric CNS tumors; however, MRI measures can only provide inference into tumor biology and molecular stratification. miRNAs are an abundant and stable nucleic acid found circulating in blood and cerebrospinal fluid (CSF) and can be utilized as a tumor biomarker.

METHODS

We hypothesized that correlating miRNA biomarkers with radiological tumor measurements may provide improved diagnostic and monitoring for patients with pediatric brain tumors. Using a cohort of 54 pediatric brain tumors including low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma we attempted to combine MRI findings and circulating miRNA data. The miRNA expression was profiled in 33 CSF and 52 plasma samples using the HTG EdgeSeq platform. Clinically acquired, multi-parametric MRI scans at time-points close to liquid biopsy collection were collected retrospectively and used to generate volumetric tumor segmentations. Machine learning methods were implemented to evaluate combinatory features.

RESULTS

We identified unique miRNA targets that significantly correlated with MRI features, clinical findings, and patient outcomes. In both CSF and plasma, miRNA expression was found to correlate with diagnosis and clinical features including tumor grade and disease burden (p < 0.05). In CSF, miRNA expression was correlated with MRI features including cystic core presence, edema, leptomeningeal disease and tumor location (p <0.05). In plasma, differences in miRNA expression were related to MRI measurements including cystic core volume, location, and leptomeningeal disease (p < 0.05). Combination of miRNA targets for plasma or CSF with imaging-based features significantly improved histology specific multimodal diagnosis predictions.

CONCLUSIONS

These results demonstrate the potential utility of miRNAs as a pediatric brain tumor biomarker which when combined with imaging features can improve minimally and non-invasive diagnostics and the subsequent management of pediatric brain tumor patients.
CNSC-03. LINKING CELL FATE DETERMINATION IN THE EMBRYONIC FOREBRAIN TO PEDIATRIC HIGH-GRADE GLIOMA
Authors: Furst Liam M , Roussel Enola M , Leung Ryan F , George Ankita M , Firestein Ron , Faux Maree C , Eisenstat David D
Published: June 2024

BACKGROUND

Pediatric high-grade gliomas are treatment resistant, usually fatal cancers encompassing diffuse midline glioma, K27-altered (DMG), and diffuse hemispheric glioma, G34R/V (DHG). Most patients harbour canonical and non-canonical mutations in histone variants H3.1 and H3.3, leading to global epigenetic dysregulation and stalled differentiation states as oligodendroglial progenitor cells (OPC) in DMG and GABAergic interneuron precursors in DHG. DLX2 is a homeobox transcription factor that directly represses OPC cell fate and promotes GABAergic interneuron cell fate and migration during early neurogenesis. Methods & Results Our lab has shown DLX2 promoter occupancy of Gad1/Gad2, and early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required for OPC differentiation in vivo. Co-expression of DLX2 with these target sequences reduces reporter gene expression in vitro, and the Dlx1/Dlx2 double knockout (DKO) mouse showed increases in Olig2, Nkx2.2, and Plp-1 expression in vivo. Transient over-expression of a Dlx2-GFP construct into murine DMG cells resulted in significant increased expression of Gad1/2 isoforms and decreased Olig2 and Nkx2.2, global restoration of H3K27me3 and loss of H3K27 acetylation, as well as a reduction in migration, invasion, and colony formation in vitro. To validate in human pHGG, we first probed an RNA-seq database containing 62 patient-derived pHGG cell lines which demonstrated an inverse correlation between DLX2 expression and OLIG1/2. Cell fate changes in DHG cell lines were evaluated by knockout of DLX2 using CRISPR/Cas9. Concurrently, OLIG1/2-expressing DMG cell lines underwent stable transfection of a DLX2-mCherry overexpression construct in conjunction with a SOX2-BFP overexpression construct, confirmed by qPCR and immunoblot. Analysis of histone H3 marks, K27M, and OPC signature genes will be compared to OPC genes from Dlx1/Dlx2 DKO mouse ganglionic eminences.

CONCLUSIONS

Manipulation of DLX2 in pHGG provides a model system for assessing the contribution of a homeobox factor to cell fate decisions regulating differentiation and tumorigenicity.
CP-02. DAYTIME SLEEPINESS AND HEALTH-RELATED QUALITY OF LIFEIN PATIENTS WITH CHILDHOOD-ONSET CRANIOPHARYNGIOMA
Authors: Mann-Markutzyk Laura V , Beckhaus Julia , Oezyurt Jale , Friedrich Carsten , Müller Hermann L
Published: June 2024

BACKGROUND

Adamantinomatous craniopharyngioma (CP) is a rare embryonal malformation originating from remnants of the craniopharyngeal duct and located in the sellar and/or parasellar area. Overall survival rates are high (92%), but frequently quality of life (QoL) is severely impaired in patients with CP involving hypothalamic structures. Tumor- and/or treatment-related hypothalamic lesions result in disturbances of circadian rhythms including increased daytime sleepiness.

METHODS

After a median follow-up interval of 10 years (range: 1-39 years), 119 patients (63 female/ 56 male) with CP, recruited in KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 between 2000 and 2022, were analysed for daytime sleepiness by Epworth scale (ES) and for QoL by EORTC QLQ-C30 questionnaire.

RESULTS

CP patients (n= 85) with pathologically increased ES score (ES score > 12) had worse QoL (p = 0.003), when compared with CP patients with normal ES score (n= 34). Pathologically increased daytime sleepiness (ES score) was negatively correlated with QoL (r= -0.395; p< 0.001). Surgical hypothalamic lesions (71% of patients) were associated with higher ES scores, whereas such impact could not be observed for presurgical hypothalamic involvement of CP (73% of patients).

CONCLUSIONS

As increased daytime sleepiness plays an important role for QoL in survivors of CP, treatment of disturbances of circadian rhythms with medication such as central stimulating agents is recommended. For prevention of increased daytime sleepiness, hypothalamus-sparing surgical treatment strategies should be considered as state of the art in patients with CP.
CP-15. LONG-TERM OUTCOMES OF PAEDIATRIC CRANIOPHARYNGIOMAS: MULTI-CENTRE COMPARATIVE STUDY
Authors: Yamaki Vitor Nagai , Sidpra Jai , Peres Bruno Santanna , Massey Flavia , Quianga Catuto Domingos Alexandre , da Borsatto Guilherme Jose Costa , Telles Joao Paulo Mota , Silva Inês Nobrega , Martinez-Barbera Juan Pedro , Biswas Asthik , Mankad Kshitij , Gan Hoong-Wei , Marcus Hani J , Jeelani Noor ul Owase , Hargrave Darren R , Matushita Hamilton , Marie Suely Kazue Nagahashi , Aquilina Kristian
Published: June 2024

BACKGROUND

Craniopharyngioma (CP) account for 80% of childhood hypothalamopituitary tumours and, though benign, their proximity to the visual pathways, hypothalamus, and pituitary incurs significant long-term neurologic and endocrine morbidity. Informed surgical decision-making has the potential to reduce morbidity and improve outcomes.

METHODS

This multicentre retrospective observational study aimed to compare long-term outcomes of CP at two paediatric neurosurgery units (GOSH, UK, and USP, Brazil), delineating management paradigms associated with better prognosis. CP treated over a 20-year period were identified and standardized clinical outcomes recorded for comparative analysis.

RESULTS

123 patients were identified (USP=52; GOSH=71). No demographic differences were identified between series (mean age: USP=9.2±4.6; GOSH=8.2±4.1 years). Headaches (USP=75%; GOSH=62%) and visual deficits (USP=46%; GOSH=38%) were the most common presenting symptoms. Growth hormone deficiency at presentation was more common in the USP cohort (USP=62.5%; GOSH=35%; p=0.009). There was significantly more hypothalamic invasion in the GOSH cohort (Paris grade 2: GOSH=67.0%; USP=37.5%; p=0.026), but significantly larger cystic volumes in the USP cohort (USP=27.5±37cm3; GOSH=10.5±8.9cm3;p=0.004). These differences led to different surgical approaches, with more subtotal resections at USP (78%) and more cyst aspirations at GOSH (62%). 80% of patients at GOSH received RT compared to 32% at USP. Mean follow-up at GOSH was 7.5±4.8 years compared to 10.1±5.6 years at USP. Cognitive outcome did not vary. GOSH cohort presented higher rates of levothyroxine replacement (USP=67%; GOSH=86%;p=0.017). GOSH exhibited better hypothalamic outcomes (p=0.08) and better visual outcomes (field deficits: GOSH=44%; USP=66%;p=0.01). In multivariate analysis (n=123), subtotal/gross-total resection (OR0.17; 95%CI:0.05-0.55;p<0.01) and older age at diagnosis (OR0.91, 95%CI:0.82-0.99;p=0.04) were associated with longer progression-free survival.

CONCLUSIONS

Comparative analysis of two large craniopharyngioma series identified different paradigms of surgical management driven by clinical-radiological presentation with similar long-term outcomes. Subtotal/gross-total resection was not related to worse clinical outcome or better progression-free survival.
DIPG-04. THE BENEFIT OF CRANIOSPINAL IRRADIATION (CSI) RESCUE IN PHASE 2 RANDOMIZED STUDY OF RADIOTHERAPY (RT), CONCOMITANT NIMOTUZUMAB AND VINORELBINE AND RE-IRRADIATION AT RELAPSE, VERSUS MULTIPLE ELECTIVE RADIOTHERAPY COURSES WITH CONCOMITANT VINORELBINE AND NIMOTUZUMAB FOR NEWLY DIAGNOSED CHILDHOOD AND ADOLESCENCE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Massimino Maura , Biassoni Veronica , Mastronuzzi Angela , Schiavello Elisabetta , Barretta Francesco , Quaglietta Lucia , Milanaccio Claudia , Pecori Emilia , Cacchione Antonella , Ruscio Valentina Di , Chiesa Silvia , Scimone Giuseppe , Barra Salvina , De Martino Lucia , Nigro Olga , Ramaglia Antonia , Picariello Stefania , Verrico Antonio , Vallero Stefano , Mussano Anna , Vennarini Sabina , Calareso Giuseppina , Podda Marta , Gattuso Giovanna , Cinalli Giuseppe , Antonelli Manila , Dossena Chiara , Buttarelli Francesca Romana , Gianno Francesca , Minasi Simone , Modena Piergiorgio , De Cecco Loris
Published: June 2024

BACKGROUND

This trial evaluated feasibility,response,PFS/OS of a randomization comparing two different RT schedules for DIPG while administering the same systemic treatment. We moreover evaluated the benefit of craniospinal irradiation(CSI) in case of disseminated(D) relapse.

METHODS

Patients: 2-21 years-old with at least radiologically verified DIPG (MRI blindly reviewed at diagnosis,every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy required if atypical imaging, also allowed after adequate consensus.Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm was full brainstem/focal tumor site RT at total dose of 54Gy(1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination CSI at 36Gy was offered.Experimental(SP) arm included three elective courses of RT at defined time-points(36Gy, 19.8Gy and 19.8Gy) with reirradiation for relapse at 9 Gy/36 Gy as above described. Incidences of local(L) and D progression were assessed in a competing risk setting.

RESULTS

55 patients were included from 4 Italian centers,27 in ST,30 males, median age 7.1 years. Median follow-up 39.1 months. Fifteen patients needed a shunt,13 during treatment;23 were biopsied,in 21 according to local protocols.22/23 tumors had H3.3K27 mutation. 53 relapsed, 34 L,13 D,6 L+D.Fifteen/19 with a D component receiving CSI had a median survival of 7.6 months after relapse, significantly higher than that of the 4 without CSI(median 2.9 months,P=0.020). Patients submitted to biopsies had more D(P=0.017) and less L progression(P=0.058). SP irradiation and any reirradiation at relapse were feasible and never produced significant radionecrosis.Median EFS/OS for the whole series were 8.4/14 months, respectively; not significantly different between patients with local vs. disseminated relapses.

CONCLUSIONS

Reirradiation, even if CSI, confirmed feasible and benefitted patients OS.Randomization results will be later reported.
DIPG-15. NOVEL CNS SENSING SYNNOTCH-CAR T CELLS FOR TARGETING DIFFUSE MIDLINE GLIOMA
Authors: Lakshmanachetty Senthilnath , Simic Milos , Haegelin Jeffrey , Watchmaker Payal , Long Haoyu , Deucker Jason , Zhu Robert , Sheperd Chanelle , Yu Wei , Ng Ben , Wang Yuan , Troyanskaya Olga , Cardarelli Lia , Sidhu Sachdev , Lim Wendell , Okada Hideho
Published: June 2024

BACKGROUND

Diffuse midline glioma (DMG), including Diffuse intrinsic pontine glioma (DIPG), is an aggressive brain tumor in children with limited treatment options. Recent developments of phase 1 clinical trials have shown early promise for chimeric antigen receptor (CAR) T cells in patients with DMG/DIPG. However, several barriers such as the absence of tumor-specific antigens, restricted trafficking to the tumor site, and poor persistence hinder the full therapeutic potential of CAR T cell therapy in DMG/DIPG.

METHODS

To safely target the glioma-associated antigens (GAAs) without attacking nomal tissues expressing the same antigens, we adopted a novel synthetic Notch (synNotch) receptor system and engineered T cell circuits employing a “prime-and-kill” strategy. In this system, a synNotch receptor recognizing the priming antigen, Brevican (BCAN), exclusively expressed on cells in the central nervous system (CNS) but not on non-CNS cells, locally induces the expression of a tandem CAR against GAAs, ephrin type A receptor (EphA2) and interleukin-13 receptor a2 (IL13Ra2), there by homogenously eliminating DMG/DIPG cells.

RESULTS

The α-BCAN synNotch⋄α-EphA2/IL-13Rα2 CAR (B-SYNC) T cells efficiently killed DMG/DIPG (BT-245, SF8628, SU-DIPGXIII, and SU-DIPGXVII) cells in vitro in the presence of priming cells (K562 cells expressing BCAN). Moreover, a single intravenous infusion of B-SYNC T cells significantly (P< 0.001) prolonged the survival of immunodeficient mice bearing aggressive, orthotopic SF8628 DIPG xenografts and completely eradicated the tumor in more than 50% (4/7) of mice. Strikingly, we observed excellent homing, priming, activation, and persistence of B-SYNC T cells in the brain stem of mice bearing SF8628 xenografts. In contrast, constitutively active α-EphA2/IL-13Rα2 CAR T cells or untransduced T cells demonstrated a failure to migrate to the brain stem and improve the survival of mice.

CONCLUSIONS

Collectively, our findings strongly support the development of clinical trials evaluating the efficacy of B-SYNC T cells in DMG/DIPG patients.