bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospects for the detection of very-high-energy pulsars with LHAASO and SWGO
Authors: Hu Quan , Zhang Yi , Duan Kaikai , Zeng Houdun 
Published: June 2024

ABSTRACT
Pulsations from the Crab pulsar have been detected by the MAGIC telescopes at energies up to 1.5 TeV, and the pulsed emission from the Vela pulsar was detected by H.E.S.S., reaching tens of TeV. These discoveries, along with the proposed additional emission due to inverse Compton scattering at TeV energies, lead us to consider suitable candidates for detection with current and future extensive air show (EAS) experiments at very-high-energy (VHE; 0.1$-$100 TeV) ranges. Leveraging energy spectrum data from pulsars as observed by Fermi and Imaging Atmospheric Cherenkov Telescopes (IACTs) and considering the sensitivities of both LHAASO and SWGO, this study evaluates their detectability and estimates the time required for their significant detection. Our results indicate that LHAASO could detect the Crab’s pulsed signal within six years, while SWGO might detect Vela’s signal within one year. Observations of the most energetic Fermi pulsars with EAS experiments will provide insight into the nature of VHE pulsar emissions, helping us to clarify the primary characteristics of VHE pulsars.
African Liveliness as a Secular Moral Theory: Problems and Prospects
Authors: Lougheed Kirk 
Published: June 2024

Abstract
An important belief in African Traditional Religion holds that everything, both animate and inanimate objects, are imbued with an imperceptible energy known as life force. Since life force is the greatest value, it is the grounds of morality. However, it is undertheorized in contemporary African ethics, with work on personhood and harmonious relationships taking centerstage. I seek to fill this gap in the literature by further developing an entirely secular and naturalistic moral theory of life force that avoids metaphysical controversies and is known as liveliness, which was first gestured at by Thaddeus Metz (2012, 2022). I demonstrate that while a series of objections that Metz levels against liveliness affect teleological versions, they do not apply with equal force to deontological versions. Liveliness, particularly deontological versions, ought to be considered as a contender for the best African moral theory alongside those that focus on personhood or harmonious relationships.
ATRT-04. RETROSPECTIVE ANALYSIS OF 271 RELAPSED AND REFRACTORY ATYPICAL TERATOID RHABDOID TUMORS – COMBING DATA FROM INTERNATIONAL COHORTS IN A COLLABORATIVE EFFORT
Authors: Steinbügl Mona , Rosenberg Tom , Desai Kavita , Govender Dinisha , Liu Anthony Pak Yin , André Nicolas , O’Hare Patricia , Nysom Karsten , Bourdeaut Franck , Fisher Michael J , Margol Ashley , Reddy Alyssa T , Frühwald Michael C 
Published: June 2024

Abstract

BACKGROUND
Relapse or refractory (r/r) disease is common in atypical teratoid rhabdoid tumors (ATRT), yet little is known about clinical patterns, prognostic factors, and outcomes beyond individual case reports. Large representative cohorts are missing, impeding the interpretation and design of clinical trials for r/r ATRT.

METHODS
We retrospectively collected data on r/r ATRT from centers in the US, Europe, Hong Kong, and Australia, including patients previously enrolled in clinical trials (e.g., COG ACNS0333, DFCI 02-294) or the prospective EU-RHAB registry. Inclusion criteria were relapse (recurrence after complete remission (CR)) or progression (tumor growth or new metastasis without previous CR) following at least one course of chemotherapy.

RESULTS
271 patients were analyzed; median age was 16 months (m) at diagnosis (0-233). Molecular subgroup status was available in n=118. Relapse (44%) or progression (54%) occurred after a median of 8m. Only 34% of events were localized at the primary tumor site; distant metastasis only (31%) and combined events (31%) were more common. Salvage treatment was multimodal with systemic pharmacotherapy (n=176), surgery (n=71), high-dose chemotherapy (n=19), and/or radiotherapy (n=110). Targeted treatment included epigenetically targeted drugs (n=45), alisertib (n=11), immunotherapy (n=10) and metronomic therapy (n=45). 1-year overall survival (OS) following an event was 29.6±2.8%. Log-rank test suggested subgroup status as a prognostic factor. (TYR vs. non-TYR: 30 vs. 21w OS, p&lt; 0.05; MYC vs non-MYC: 14 vs. 25w OS, p&lt;0.05). OS was significantly inferior after progression compared to relapse (19 vs. 33w, p&lt;0.05) and in patients with rhabdoid tumor predisposition syndrome (18 vs. 25w, p&lt;0.05).

CONCLUSION
Our data confirm the poor prognosis of r/r ATRT. However, intense multimodal treatment is feasible, and molecular characteristics are potentially clinically relevant. Results from this analysis offer a robust foundation for prospective clinical trials and therapeutic algorithms for r/r ATRT.
ATRT-10. ANTI-B7-H3 CHIMERIC ANTIGEN RECEPTOR NK CELLS SHOW ANTIGEN SPECIFIC CYTOTOXICITY AGAINST ATYPICAL TERATOID/ RHABDOID TUMORSIN VITRO ANDIN VIVO
Authors: Choe Jun , Chakravarti Sachiv , Holl Natalie , Rahnama Ruyan , Zinsky Megan , Jones Danielle G , Vorri Stamatia , Modi Arjun , Raabe Eric H , Bonifant Challice L 
Published: June 2024

Abstract

BACKGROUND
Atypical teratoid/rhabdoid tumors (AT/RTs) are the most common malignant CNS tumor in infants. AT/RT patients have a 5-year overall survival rate of ~35% and high rates of relapse, emphasizing a dire need for new safe and effective therapies. These therapy-resistant tumors frequently overexpress cell surface molecule B7-H3 (CD276). CAR-NK cells have several advantages over CAR-T cells. NK cells can be obtained from healthy donors and produced as an “off-the-shelf” product. NK cells also have a lower risk of inflammatory toxicity and graft-versus-host disease compared to T-cells when transferred across the HLA barrier.

METHODS
We have designed a library of variable affinity B7-H3-targeted CARs, produced γ-retroviral vector, and used this for generation of B7-H3 CAR-NK cells. We verified B7-H3 expression in a panel of AT/RT cell lines, and further engineered firefly luciferase expressing AT/RT (CHLA06.ffLuc, BT12.ffLuc, BT37.ffLuc) as well as a CHLA06-derived B7-H3 knockout. We developed an orthotopic CHLA06.ffLuc xenograft model. We tested CAR-NK cell functionality using in vitro co-culture and cytotoxicity assays. In vivo study was performed in our xenograft with intratumoral delivery of CAR-NK cells.

RESULTS
B7-H3 targeted CAR-NK cells demonstrate target-specific cytotoxicity when compared to untransduced NK cells (36.8±12.5% vs. 72.4±24.2% at effector:target ratio of 1:1, n=3). CRISPR/Cas9 mediated knockout of B7-H3 in target cells abolished the difference in CAR vs. no-CAR NK-mediated target killing. When delivered intracranially to CHLA-06 orthotopic xenograft bearing mice, B7-H3 CAR NK cells eliminate tumor cells and prolong survival, whereas unmodified NK cells did not (log-ranked median survival = 20 vs. 84 days, p&lt;0.0001).

CONCLUSIONS
Targeting AT/RTs with an anti-B7-H3 CAR-NK cell therapy may provide a safe and effective treatment for patients who have extremely limited therapeutic options. Direct intracranial injections of cell therapies into pediatric patients is currently being explored in clinical trials.
ATRT-11. IRS-III: LONG-TERM FOLLOW-UP SHOWS FAVORABLE OUTCOMES AND DURABLE RESPONSES FOR LOCALIZED ATYPICAL TERATOID RHABDOID TUMOR (ATRT)
Authors: Desai Kavita , Rosenberg Tom , Power Phoebe , Manoharan Neevika , Nagabushan Sumanth , Green-Murphy Audrey , Ziegler David S , Li Yimei , Fisher Michael J , Chi Susan 
Published: June 2024

Abstract

BACKGROUND
IRS-III-based chemotherapy is a long-standing treatment approach for ATRT, which mostly affects infants under the age of 3. We provide long-term outcomes from three high-volume pediatric centers, including a subgroup of patients treated with “moderately-delayed” radiation therapy (RT).

METHODS
We performed a retrospective analysis of 60 patients treated between 1999-2021. Patients at Boston and Sydney Children’s Hospitals received per-protocol early chemoradiation during induction cycles 3-4, while patients at Children’s Hospital of Philadelphia received moderately-delayed RT with temozolomide post 6 induction cycles. Demographic, clinical and outcome data were collected.

RESULTS
Median age at diagnosis was 2.3 years (range:0.5-19.5) with median follow-up 2.7 years (range:0.1-15.5); however, 20/60 patients were followed &gt; 5 years (median 10.4, range:5.1-15.5). Thirty-six patients (60%) underwent gross or near-total resection; 14 (23%) had metastatic disease. Seventeen (28%) did not receive RT due to progression, toxicity, or provider discretion; 27 (45%) received focal and 17 (28%) craniospinal RT. For the entire cohort, 5- and 10-year PFS were both 30% (95%CI: 19-42). OS were 38% (95%CI: 27-51) and 31% (95%CI: 19-43), respectively. For patients with localized disease, 5-year PFS and OS were 38% (95%CI: 24-52) and 45% (95%CI: 30-56), respectively. Patients with metastatic disease had 5-year PFS and OS of 0% and 19% (95%CI: 3-43), with no long-term survivors. In multivariate analysis, RT was a statistically significant prognostic factor. However, treatment field (focal vs. CSI), RT timing (early vs. moderately-delayed), patient age, resection extent, or metastatic status were not significant.

CONCLUSIONS
Our results suggest that IRS-III should remain a standard of care approach for localized ATRT, based on the favorable survival outcomes with the longest follow up of any published ATRT regimen to date. In addition, it highlights the importance of RT for localized disease and proposes it can be given after induction without compromising outcomes, reducing treatment-related toxicity.
ATRT-12. EXPLORING FGFR INHIBITION AND COMBINATION THERAPIES FOR ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Senfter Daniel , Freund Julia , Mager Leah , Bruckner Katharina , Stepien Natalia , Mayr Lisa , Jaunecker Carola N , Laemmerer Anna , Kirchhofer Dominik , Kuess Peter , Eckert Franziska , Dorfer Christian , Kool Marcel , Haberler Christine , Berger Walter , Lötsch-Gojo Daniela , Madlener Sibylle , Gojo Johannes 
Published: June 2024

Abstract

BACKGROUND
Atypical teratoid/rhabdoid tumors (ATRTs) are aggressive pediatric brain neoplasms characterized by an inactivation of the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. Based on epigenetic profiling ATRTs can be divided into four different molecular subgroups. Despite improvements in treatment strategies, the prognosis for ATRT patients remains dismal. The FGF/FGFR signaling pathway plays a crucial role in many physiological processes, including embryonic development, tissue repair, angiogenesis. Dysregulation of the signaling axis is driving tumorigenesis. Targeted therapeutic approaches, particularly FGFR inhibitors, have demonstrated potential in enhancing treatment outcomes for various tumors, including pediatric brain tumors.

METHODS
We used bulk and single-cell RNA sequencing (scRNA-seq) data to examine the expression patterns of FGF family members in ATRTs. Subsequently, we conducted in vitro analysis on a panel of FGFR inhibitors and combination treatments.

RESULTS
Transcriptomic analysis of more than 130 ATRT tissues samples, revealed a widespread expression of FGFR1 and FGFR2 across all ATRT subtypes. Notably, FGFR1 displayed distinctly elevated expression in ATRT-SHH, surpassing levels seen in other ATRT subtypes and brain tumor types. Utilizing scRNA-seq data of murine ATRT models, we elucidated an autocrine FGFR signaling loop. To assess the therapeutic feasibility of targeting FGFR, we evaluated a panel of FGFR inhibitors, currently in clinical development, across 10 in house established patient-derived cell models (6 ATRT-MYC, 3 ATRT-SHH, 1 ATRT-TYR), revealing sensitivity in a nanomolar to a low-micromolar range. We further explored combination therapies, demonstrating that Erdafitinib, the most effective inhibitor when combined with Abemaciclib and radiation, exhibited enhanced synergistic effects in 2D as well as in 3D tumoroid models. Investigations towards testing these combinations in an organoid co-culture system, along with in vivo models are ongoing.

CONCLUSIONS
This study emphasizes the prospect of combining FGFR inhibition with radiation and CDK4/6 inhibition as a therapeutic target for ATRTs.
ATRT-13. NOVEL ACYLFULVENE LP-184 SYNERGIZES WITH RUCAPARIB TO KILL AT/RT CELLS
Authors: Tindall Abigail , Kwon Abby , Eberhart Charles , Raabe Eric 
Published: June 2024

Abstract

BACKGROUND
Atypical Teratoid Rhabdoid Tumor (AT/RT) is a pediatric brain cancer with survival rates of less than 40%. Illudins are a novel class of DNA-damaging alkylating agents. LP-184, an investigational synthetic acylfulvene analog currently in a first-in-human Phase 1 trial, exhibits enhanced ability to penetrate the brain and damage DNA in tumor cells. We hypothesized that LP-184 would synergize with PARP inhibitors such as rucaparib which inhibit DNA repair. The combination of these therapies could be a promising treatment option for AT/RT.

METHODS
We tested LP-184 against the AT/RT cell lines BT37, CHLA06, CHLA05, and CHLA266. Cell viability assays were conducted by flow cytometry. Immunofluorescence was performed to visualize CC3 and BrdU. Western blots were performed to determine c-PARP and p-RB protein levels. Synergy experiments were performed using cell growth inhibition as the readout and quantified using the SynergyFinder online computational tool.

RESULTS
LP-184 suppressed AT/RT proliferation at nanomolar concentrations as measured by BrdU immunofluorescence and pRB western blots (BrdU BT37 p=0.0001, CHLA06 p=0.0001, CHLA05 p=0.033 50 nM concentration of LP-184 compared to DMSO control). Furthermore, LP-184 showed strong synergy with the PARP inhibitor rucaparib. Viable cell count was reduced by as much as 80% in combination compared to DMSO control (BT37 p=0.0001, CHLA06 p=0.0002, CHLA05 p=0.0077). Combination therapy decreased proliferation as measured by immunofluorescence and confirmed by pRB western blots (BrdU BT37 p=0.0004, CHLA06 p=0.0033, CHLA05 p=0.0154 compared to DMSO control). LP-184 and rucaparib induced apoptosis as measured by cleaved caspase 3 (CC3) and cPARP western blots (BT37 p=0.0002, CHLA06 p=0.0117, CHLA05 p=0.0001 %CC3+ compared to control). Survival studies in vivo are underway to test single agent and combination therapies of LP-184 and rucaparib in AT/RT.

CONCLUSION
LP-184 and rucaparib together could provide a compelling clinical option for patients with this poor-prognosis brain tumor.
ATRT-15. COMBINING THE PI3K INHIBITOR PAXALISIB WITH NUCLEOSIDE ANALOG GEMCITABINE TO IMPROVE SURVIVAL OF ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Findlay Tyler , Malebranche Kristen , Geethadevi Anupa , Eberhart Charles , Rubens Jeffrey , Raabe Eric 
Published: June 2024

Abstract

BACKGROUND
Atypical teratoid/rhabdoid tumors (ATRT) have a dismal overall survival. Targeting the mTORC1/2 pathway kills ATRT tumor cells and increases the survival of mice bearing orthotopic xenografts. Paxalisib is a brain penetrant PI3K inhibitor that is in pediatric clinical trials for diffuse midline glioma. Paxalisib activates the integrated stress response (ISR) in ATRT. Consistent high-level activation of the ISR leads to cell death. We hypothesize paxalisib will synergize with the DNA-damaging agent gemcitabine, which also triggers the ISR, to over-activate this pathway and drive ATRT apoptosis.

METHODS
We analyzed ISR gene expression following mTOR inhibition via RNA-seq. Children’s Brain Tumor Network (CBTN) provided comparative data on ISR genes in ATRT and other pediatric brain tumors. Paxalisib/gemcitabine effects were evaluated through cell-based assays, western blot for ISR markers, and survival in three murine models.

RESULTS
ATRT have high baseline expression of ISR genes (CBTN: ATF4, eIF2α), and mTOR inhibition leads to activation of ISR genes (ATF4, CHOP, PPP1R15A, p&lt;0.05). Paxalisib monotherapy significantly extends median survival in murine models compared to vehicle controls (CHLA-06: 40 to 54 days, p=0.001; BT-12: 21 to 35 days, p=0.05). Paxalisib/gemcitabine therapy synergized to slow cell growth and induce cell death (SynergyFinder BLISS score in five ATRT cell lines). Combination therapy leads to ISR activation (western blot: p-eIF2α, ATF4, CHOP). Combination slowed tumor growth (bioluminescent imaging) and led to significant extension of survival in orthotopic xenograft models (CHLA-06: 22 to 82.5 days; BT-37 56-day vehicle median survival while undefined combination survival). A third model is ongoing and showing similar results.

CONCLUSIONS
Paxalisib/gemcitabine therapy shows potential for targeting ATRT by over-activating the ISR. Our findings prompted the Pediatric Neuro-Oncology Consortium to consider this combination for inclusion in an upcoming clinical trial targeting relapsed/refractory ATRT, offering a novel approach to treat this aggressive tumor.
BIOM-09. TOWARDS CLINICAL IMPLEMENTATION OF LIQUID BIOPSY ANALYSIS FOR PAEDIATRIC BRAIN TUMOUR PATIENTS – A PAN-EUROPEAN EFFORT FOR STANDARDIZATION
Authors: Simon Nike , Maass Kendra K , Pokorná Petra , Stepien Natalia , Rettenmeier Johanna , Saijonmaa Oskar , Fischer Tom T , Senfter Daniel , Madlener Sibylle , Giraud Géraldine , Tham Emma , Scarpini Cinzia G , Murray Matthew J , Hulleman Esther , Clifford Steven C , Pfister Stefan M , Pajtler Kristian W , Gojo Johannes 
Published: June 2024

Abstract

BACKGROUND
Liquid biopsies (LBs) allow for analysis of tumour-derived molecules, such as cell-free DNA (cfDNA) and microRNAs (miRNAs), complementing cancer diagnostics, therapy monitoring, and minimal residual disease detection. While circulation-based LB has benefit for extracranial tumour entities, peripheral blood has not historically been a reliable source for diagnosis and disease-monitoring in brain tumours. For these tumours, cerebrospinal fluid (CSF) analysis is better suited for detection despite being a more invasive procedure. However, standardized protocols for sample collection and pre-analytical parameters for these LBs currently are limited.

AIM
We aim to establish an evidence-based gold standard protocol for cfDNA and miRNA analyses from CSF in paediatric brain tumour patients. In addition to higher compliance in trial-related CSF sampling, this initiative seeks to facilitate identification of clinically relevant indications and time-points for collection, thereby paving the way for well-informed, routine CSF molecular diagnostics.

METHODS AND RESULTS
We have initiated the Liquid Biopsy Working Group within the framework of the International Society of Paediatric Oncology Europe Brain Tumour Group (SIOPE-BTG). Available literature on LB in brain tumours was critically assessed regarding pre-analytical parameters, downstream analyses and LB assay performance. To directly evaluate confounding by pre-analytical factors, we experimentally compared the impact of CSF sampling sites, storage conditions, and different pre-processing protocols. cfDNA and miRNA yields, purity, and the fraction of tumour-derived material were selected as read-outs and correlated with tumour tissue information. To prepare for clinical translation, we consulted clinical paediatric brain tumour trial coordinators to identify major bottlenecks for CSF sampling in routine clinical practice. In addition, clinical practitioners and patient/ parent representatives have been consulted to comprehensively represent the perspectives and needs of all stakeholders. Together, results of this collaborative effort will be fundamental to the successful clinical integration of LBs to improve the future management of paediatric brain tumour patients.
CNSC-01. UNDERSTANDING PEDIATRIC BRAIN TUMOR CHEMOTHERAPY INDUCED LONG-TERM DEFICITS IN HIGH-ORDER NEUROCOGNITIVE AND SENSORIMOTOR FUNCTION
Authors: Singh Anand K , Bertrand Renae , Mahalingam Rajasekaran , Zimbwa Shungu , Kasm Khalil A Ahmad , Pan Yuan 
Published: June 2024

Abstract

BACKGROUND
Because of major advancements in cancer treatment especially chemotherapy, 85% of children with cancer are predicted to survive for 5 years or more. However, chemotherapy can cause long-term health problems when childhood cancer survivors enter adulthood (known as late effects). The neurocognitive features of these late effects (chemobrain) include trouble in concentrating, memorizing, and decreased processing speed, and results in lower IQ and academic achievement, poor hand-eye coordination, and slower development over time. Despite such a negative impact on the quality of life of cancer-surviving children, the mechanism is poorly understood and there is no FDA-approved drug to prevent or cure these side effects.

METHODS
To gain a better understanding of the mechanism underlying chemotherapy-induced cognitive impairments, we developed a pre-clinical model using carboplatin in juvenile mice to study long-term neurological defects. We have tested the capacity of different doses of carboplatin and its long-term effect on cognitive and sensorimotor function and performed single nuclear RNA sequencing (snRNAseq) of the hippocampus.

RESULTS
Our preliminary data demonstrated dose-dependent deficits in executive and sensorimotor function 7-9 weeks after carboplatin administration in the mice of both sexes. snRNAseq of the hippocampus showed changes in the glial cell number as well as genes associated with oxidative phosphorylation and neurodegeneration at early and late time points.

CONCLUSIONS
This study established a preclinical model that can be leveraged to mechanistically understand the long-term neurocognitive side effects of brain tumor chemotherapy during childhood. Future studies will aim to identify potential targets to prevent and/or treat the neurotoxic effects of cancer treatment in pediatric patients.
CP-03. EXTRACELLULAR MATRIX REMODELING REVEALS NON-CELL AUTONOMOUS TUMOR FORMATION MECHANISM IN ADAMANTINOMATOUS CRANIOPHARYNGIOMAS
Authors: Jeang John A , Jomaa Danny , Novikov Dana , Tsai Jessica W , Apps John R , Manshaei Saba , Prince Eric , Hankinson Todd C , Martinez-Barbera Juan-Pedro , Bandopadhayay Pratiti 
Published: June 2024

Abstract
Adamantinomatous Craniopharyngioma (ACP) is a rare pituitary tumor of the sellar region, with a bimodal presentation pattern in children and middle-aged adults. ACPs are primarily driven by a mutation in CTNNB1 that prevents beta-catenin from degrading properly, resulting in accumulation in the nuclei of epithelial whorl-like structures sometimes referred to as cluster cells. Clinical management is challenging due to the location of the tumor, such that complete surgical resection is often not possible so radiation therapy, which can lead to high morbidity, is also used. Greater insight into these tumors can help develop less damaging treatment strategies. In this analysis we have employed single-cell RNA sequencing technology to examine seven pediatric human ACPs (28594 cells). Using consensus non-negative matrix factorization, and traditional marker genes, we have partitioned our dataset into several cell types including cluster cells, palisading epithelial cells, microglia, T-cells, B-cells, plasma cells, and fibroblasts. Though cluster cells themselves do not actively proliferate, we believe the complex inter-cellular signaling is responsible for tumor formation. We propose a model in which malignant fibroblasts form from the existing epithelium and remodel the extracellular matrix (ECM) creating a stiffened tumor microenvironment. To support this claim we show activation markers suggesting myofibroblast differentiation, the expression of EMT signatures indicating a transformation from epithelial to fibroblast, and RNA velocity analysis that demonstrates lineage tracing. We believe that the remodeling of the ECM is a wound healing response influenced by TGF-beta, SPP1, and other signaling pathways. Our analysis of ACPs reveals the role of the tumor microenvironment in the formation of these tumors.