bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Reconstruction of the Successful Establishment of a Feralized Bovine Population on the Subantarctic Island of Amsterdam
Authors: Gautier Mathieu , Micol Thierry , Camus Louise , Moazami-Goudarzi Katayoun , Naves Michel , Guéret Elise , Engelen Stefan , Lemainque Arnaud , Colas François , Flori Laurence , Druet Tom 
Published: June 2024

Abstract
The feral cattle of the subantarctic island of Amsterdam provide an outstanding case study of a large mammalian population that was established by a handful of founders and thrived within a few generations in a seemingly inhospitable environment. Here, we investigated the genetic history and composition of this population using genotyping and sequencing data. Our inference showed an intense but brief founding bottleneck around the late 19th century and revealed contributions from European taurine and Indian Ocean Zebu in the founder ancestry. Comparative analysis of whole-genome sequences further revealed a moderate reduction in genetic diversity despite high levels of inbreeding. The brief and intense bottleneck was associated with high levels of drift, a flattening of the site frequency spectrum and a slight relaxation of purifying selection on mildly deleterious variants. Unlike some populations that have experienced prolonged reductions in effective population size, we did not observe any significant purging of highly deleterious variants. Interestingly, the population’s success in the harsh environment can be attributed to preadaptation from their European taurine ancestry, suggesting no strong bioclimatic challenge, and also contradicting evidence for insular dwarfism. Genome scan for footprints of selection uncovered a majority of candidate genes related to nervous system function, likely reflecting rapid feralization driven by behavioral changes and complex social restructuring. The Amsterdam Island cattle offers valuable insights into rapid population establishment, feralization, and genetic adaptation in challenging environments. It also sheds light on the unique genetic legacies of feral populations, raising ethical questions according to conservation efforts.
Decolonizing “Decolonization” and Knowledge Production beyond Eurocentrism
Authors: Onyebuchi Eze Michael 
Published: June 2024

Abstract
I historicize decolonial theories within the context of epistemic contestations and knowledge production in Africa. I offer a critical appraisal of decolonization as simulated within Western academic institutions and argue that the current tempo of decolonization movements is by no means an accident of history; it is, in fact, a residual narrative of colonial epistemology. I offer internal critique and discuss the limitations of decolonization as an intellectual strategy, before addressing how Western academics have appropriated the discourse in a manner fitting an intellectual crusade. The decolonial scholar is, at the same time, perpetuating the mandate of colonial epistemology by substituting coloniality with subjective displacement. Finally, I suggest a modest proposal for adopting a new framework that admits the epistemic virtues of decolonization while eschewing its limitations and internal contradictions. My argument is that decolonization studies, as understood in contemporary African philosophy, has remained afflicted with the same disease it seeks to cure by (i) uncritical affiliation with historical generalizations, (ii) failure to recognize that history is no location of innocence and (iii) recolonization of non-Western ontologies through epistemic imperialism and network legitimation.
ATRT-05. AGE ABOVE 12 MONTHS, ABSENCE OF SYNCHRONOUS, MULTIFOCAL DISEASE AND PATHOGENIC GERMLINE VARIANTS AT C-TERMINI ARE POSITIVE PROGNOSTIC FACTORS IN CHILDREN WITH RTPS1 (RHABDOID-TUMOR-PREDISPOSITION-SYNDROME)
Authors: Fruehwald Michael C , Boros Matej , Dahlum Sonja , Bens Susanne , Johann Pascal D , Kachanov Denis , Hauser Peter , Kratz Christian P , Hernaiz-Driever Pablo , Eyrich Matthias , Sumerauer David , Milde Till , Reinhard Harald , van de Wetering Marianne , Gil-da-Costa Maria Joao , Elisabetta Schiavello , Kerl Kornelius , Furtwaengler Rhoikos , Kordes Uwe , Gerss Joachim , Hasselblatt Martin , Nysom Karsten , Nemes Karolina 
Published: June 2024

Abstract

BACKGROUND
Rhabdoid-Tumor-Predisposition-Syndrome is due to germline mutations in SMARCB1 (rarely SMARCA4). We pursued a comprehensive clinical and (epi-)genetic characterization of RTPS families.

METHODS
90 affected children from 16 countries were compared to 252 with sporadic rhabdoid tumors (01/2004 - 01/2021). Tumors and blood were examined for structural or single nucleotide variants (SV, SNV) in SMARCB1/SMARCA4. In 83% (70/84) of RTPS1-patients complete genetic data were available. Trio-exome (n=25) and 850k-methylation analysis of tumors (52/84) and blood (n=51), parents (n=44) and unaffected siblings (n=4) was performed.

RESULTS
RTPS1 and 2 were diagnosed in 84 (48 females, 36 males) and 6 patients respectively. Median age at diagnosis (RTPS1 only) was 5 (0 – 203) months (18 months, 0-211 in controls, p&lt;0,001). ATRT were present in 55% (46/84), extracranial, extrarenal malignant RT (eMRT) and RT of the kidney (RTK) in 8% (7/84). 26% (22/84) presented with synchronous tumors (SYN). Homozygous SVs were less frequent in the RTPS-tumors [20% (14/84) vs 47% (82/174), p&lt;0,001]. ATRT-MYC was significantly more common among RTPS1 while ATRT-SHH was less common. Trio blood DNA-methylation analysis separated samples of parents but not siblings from RTPS patients. Likely (DNA-methylation) age was a major confounder. The analysis of trio-exomes is ongoing. 5-year-OS and -EFS in RTPS1-patients were 18,4±4.5% and 14±3,9%, (controls: 48,2 ±3,5%, 40,3±3,2%). VOD (venoocclusive disease) was significant in patients &lt; 2 months [18,5% (12/65) vs. 3,3% (3/92), p=0.005]. RTPS1-patients rarely achieved a CR [32% (27/84) vs. 52% (129/249), p=0,002]. In an adjusted multivariate model prognostic factors were male sex [HR: 1.7 (1.0 – 2.9)], age ≤12 months [HR: 2.1 (1.0 – 4.3)], and diagnosis of ATRT [HR: 0.6 (0.3 – 0.9)].

CONCLUSION
We describe significant positive outcome predictors such as age &gt;12 months, absence of SYN, diagnosis of ATRT, localized disease, PGV located at C-termini and female sex in RTPS1-patients.
ATRT-06. PEDIATRIC INI1-NEGATIVE ATYPICAL TERATOID RHABDOID TUMORS TREATED WITH TAZEMETOSTAT AS MAINTENANCE THERAPY IN THE RELAPSE SETTING: AN ITALIAN SINGLE-CENTRE EXPERIENCE
Authors: Nigro Olga , Biassoni Veronica , Schiavello Elisabetta , Casanova Michela , Bergamaschi Luca , Gattuso Giovanna , Puma Nadia , Sironi Giovanna , Colombo Valeria , Podda Marta Giorgia , Chiaravalli Stefano , Meazza Cristina , Spreafico Filippo , Ferrari Andrea , Terenziani Monica , Luksch Roberto , Massimino Maura 
Published: June 2024

Abstract

BACKGROUND
Rhabdoid tumors are aggressive malignancies, primarily affecting children ≤3 years. Common sites of primary localization are kidney, central nervous system (atypical teratoid rhabdoid tumor -AT/RT-) or soft tissues. Although high-dose chemotherapy (HD-CT) with radiotherapy (RT) has significantly increased EFS and OS rates, more than 50% of patients diagnosed with AT/RT still die of tumor progression.

METHODS
From February 2021 to January 2024 three patients with AT/RT were treated with tazemetostat after first-line treatment (complete resection, CT, RT).

RESULTS
At diagnosis, patient 1 presented with a lesion in the lamina quadrigemina and a renal mass; patient 2 and 3 with a lesion in the posterior cranial fossa. Median age at diagnosis was 8 months (3-34 months). Patient 1 died due to the progression of the disease (OS 24 months); patient 2 ended treatment with tazemetostat on December 2023; for patient 3 the treatment is still ongoing. Patient 1 started tazemetostat at the end of first-line treatment, as maintenance therapy. Before starting treatment with tazemetostat, patient 2 performed a re-irradiation on the tumor bed; patient 3 performed surgery and then RT on a new-onset spinal lesion. Median time of treatment with tazemetostat was 9 months (6-12 months). Patient 1 showed an EFS of 9 months. EFS of patients 2 and 3 has exceeded this timepoint. For patient 2 the treatment is ongoing (in total 6 months of treatment), with a complete response of the disease (CR); patient 3 ended treatment after 12 months, with a CR. Tazemetostat was overall well tolerated.

CONCLUSIONS
Despite the small number of patients, we feel able to state that the use of tazemetostat as a single agent in the relapse setting could represent a therapeutic promise as maintenance therapy. Future studies with a larger number of patients are needed to confirm this hypothesis.
ATRT-18. ALISERTIB USED IN PEDIATRIC ATRT
Authors: Fraustro Milena , Maddox Breyonna , Valdes Lilibet Fernandez , Lopez Elizabeth , Niazi Toba , Maher Ossama , Khatib Ziad 
Published: June 2024

Abstract

BACKGROUND
Atypical rhabdoid tumor (ATRT) is a rare and aggressive primary CNS tumor caused by variants or deletions in the tumor suppressor gene SMARCB1 (aka INI 1). SMARCB1 targets Aurora A kinase (AURKA), an important oncoprotein of the cell cycle. AURKA dysregulation can lead to genomic instability through its oncogenic effects. Alisertib is a selective AURKA inhibitor that has been explored for treatment in various cancers, including pediatric malignancies.

METHODS
Retrospective chart review of five patients diagnosed with ATRT, treated with Alisertib, at Nicklaus Children’s Hospital from 2019 - 2024.

RESULTS
of the 5 patients; three were females and two males, with a median age at diagnosis of 2 years. Only one patient had a germline mutation while the rest had somatic mutations. Prior to starting Alisertib therapy, all five patients received chemotherapy per multiple protocols; four patients underwent focal radiation therapy, three patients underwent resection, and two patients underwent tandem autologous transplants. All five patients were treated solely with Alisertib, median dose of 60 mg/m2 PO daily. Two patients had reduced doses during therapy secondary to cytopenia. One patient completed therapy over 13 months with partial response based on imaging. One patient presented progression of disease while on therapy and for that reason treatment was stopped. Three patients continue treatment: two with only Alisertib, one using Avastin and Sirolimus concurrently.

CONCLUSIONS
Prognosis in patients with ATRT is usually poor given its aggressive nature and high rate of recurrence despite intervention. It is important to note that treatment of ATRT is highly individualized and typically involves a combination of therapeutic modalities. While Alisertib is one of the newest treatment options, there’s limited literature of clinical improvement in patients with ATRT using this treatment. Therefore, further research on novel treatment options is warranted for the future.
BIOM-03. IMMUNO-ONCOLOGIC PROFILING OF PEDIATRIC BRAIN TUMORS REVEALS MAJOR CLINICAL SIGNIFICANCE OF THE TUMOR IMMUNE MICROENVIRONMENT
Authors: Levine Adrian , Nobre Liana , Das Anirban , Milos Scott , Bianchi Vanessa , Johnson Monique , Fernandez Nicholas , Stengs Lucie , Ku Michelle , Rana Mansuba , Fedoráková Ivana , Bennett Julie , Ramaswamy Vijay , Siddaway Robert , Tabori Uri , Hawkins Cynthia 
Published: June 2024

Abstract
With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay, including the 18-gene tumor inflammation signature (TIS) as a marker of overall immune activation, and validated this with immunohistochemistry for key cell-type markers. We used this assay, in conjunction with public data from the Pediatric Brain Tumor Atlas (PBTA), to profile a diverse range of 1382 samples in total with detailed clinical and molecular annotation. Overall among the main types of pediatric brain tumors, low-grade gliomas (LGG) had the highest inflammation levels (regardless of genetic driver alteration) and medulloblastomas the lowest. In LGG we identified three distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors, specifically that higher inflammation predicted worse outcomes. In high-grade gliomas (HGG), we observed immune activation and T-cell infiltrates in tumors that have historically been considered exclusively immune cold. There were genomic correlates of inflammation levels, with BRAF-V600E-mutant HGG having the highest inflammation levels and suggesting these may be candidates for combination MEK inhibition and immunotherapy. In mismatch repair deficient HGG, we found that high TIS was a significant predictor of response to immune checkpoint inhibition, and demonstrated the potential for multimodal biomarkers (TIS plus tumor mutation burden) to improve treatment stratification. Importantly, while overall patterns of immune activation were observed for histologically and genetically defined tumor types, there was significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.
CNSC-05. THE GABAERGIC INTERNEURONAL AND NEURAL PROGENITOR LINEAGE OF THE DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT, SHOW CALCIUM EVENTS IN THE FORM OF INTERCELLULAR WAVES AND SPONTANEOUS ELECTRICAL ACTIVITY
Authors: Cruzeiro Gustavo Alencastro Veiga , Cascio Costanza Lo , Neyazi Sina , Junior Carlos Alberto Oliveira Biagi , Haase Rebecca , Nascimento Andrezza , Frederico Stephen Charles , Sarnow Katharina , Venkataramani Varun , Liu Ilon , Huang Kun , Tang Xin , Segal Rosalind , Monje Michelle , Filbin Mariella 
Published: June 2024

Abstract

BACKGROUND
High-grade gliomas are one of the deadliest pediatric brain cancers. A diffuse subtype of hemispheric high-grade gliomas in adolescents and young adults is assigned as DHGH3G34-mutant. Notably, DHGH3G34-mutant gliomas distinctively contain cancer cell types resembling progenitors and GABAergic interneurons (eIN-like). Normal GABAergic interneurons influence neural network dynamics in the brain by communicating with other cells through the transmission of calcium and electrical signals. Our goal is to investigate the spatial organization of eIN-like glioma cells and evaluate whether they form networks and exert electrical activity relevant to tumor progression.

METHODS
Calcium Imaging: We used the Genetically encoded calcium indicator GCAMP7s with hDCX tdTomato promoter reporter construct. Voltage Imaging: We used the voltage indicator ASAP3 for detecting changes in membrane potential. Light microscopy: The whole fixed DHGH3G34-mutant PDX brain was mounted and imaged using the Zeiss Lightsheet 7 Microscope.

RESULTS
Using single-cell RNA sequencing and immunocytochemistry on DHGH3G34-mutant primary samples, we found that eIN-like cells express DCX (doublecortin) and form structures observed in ganglionic eminences. Calcium imaging revealed that DHGH3G34-mutant cells exhibit intercellular calcium waves. To track eIN-like cells, we developed a tdTomato fluorescent reporter for the DCX gene promoter activity (hDCX). Combining hDCX with GCAMP7s, we conducted calcium imaging and observed rhythmic calcium events in eIN-like cells at a frequency of 62.5mHz. Additionally, voltage imaging demonstrate that DHGH3G34-mutant cells show spontaneous action potential bursts. Furthermore, using light sheet microscopy on DHGH3G34-mutant PDX models, we observed glioma cells spreading into the contralateral hemisphere of the brain parenchyma.

CONCLUSION
DHGH3G34-mutant tumors represent highly invasive gliomas distinguished by the presence of progenitors and cells of the GABAergic interneuron lineage, exhibiting calcium waves and spontaneous action potential bursts. We are currently delving into the biological implications of these distinctive traits to gain insights into novel therapeutic strategies for the unique biology of DHGH3G34-mutant gliomas.
CP-06. PEDIATRIC CRANIOPHARYNGIOMA: SINGLE CENTER RETROSPECTIVE STUDY OF SURVIVAL, ENDOCRINOLOGIC, AND VISION OUTCOMES IN 90 PATIENTS
Authors: Ronsley Rebecca , Tam Lydia T , Do Olivia , Ermoian Ralph P , Leary Sarah E S , Werny David , Leonard Skyler , Ferreria Manuel , Ojemann Jeffrey , Ellenbogen Richard G , Lee Amy , Ruzevick Jacob 
Published: June 2024

Abstract

BACKGROUND
Craniopharyngioma is histologically benign. However, due to its location, morbidity is high and may be impacted by therapeutic approach.

METHODS
A retrospective study of patients treated for craniopharyngioma at Seattle Children’s Hospital from 1996-2023 was performed. Surgical approach, extent of resection, subsequent surgery, radiation and medical therapies, and serial surveillance magnetic resonance imaging for progression were reviewed. Five-year overall survival (OS) and progression free survival (PFS) were calculated and morbidity including endocrine and vision dysfunction was described.

RESULTS
90 patients were included of which 53(58.9%) were male. Median age at diagnosis was 8.70 (range 1.39-25.17) years. Surgical approach included endoscopic (N=24), craniotomy (N=64), and combined (N=2). Extent of resection was biopsy N=2, subtotal resection N=7, near total resection N=38, gross total resection N=30. Pathology was adamantinomatous subtype in all cases and 68 had a documented CTNNB1 alteration and 3 had a BRAF alteration in those with molecular analysis. 5-year OS was 96.1% (SE 0.13) and 5-year PFS was 51.9% (SE0.21), with median follow-up of 97 months. Transcranial compared to endoscopic endonasal approach was associated with increased risk of progression (62% vs 30%, OR 1.23). 34 patients were treated with radiation upfront (N=19) or at progression (N=15). 55% of patients at diagnosis and an additional 30% in follow up had pituitary hormone dysfunction. Hypothalamic obesity was documented in 31% of patients and varied by surgical approach. At presentation, ophthalmologic abnormalities included optic nerve edema (18%) and optic nerve pallor (24%) and 30% had abnormal visual acuity. Following initial surgery, 50% had improvement in visual acuity, 35% stable and 15% had worsened visual acuity.

CONCLUSIONS
Upfront surgical strategy may impact risk of disease recurrence; however, its relationship to long term morbidity is not clear. Further work to delineate therapeutic strategies and their relationship to morbidity in this patient population is needed.
CP-09. HTDS ON NOVEL CELL LINES IDENTIFIED BETA-CATENIN INHIBITOR TEGATRABETAN AND PROTEASOME INHIBITOR BORTEZOMIB AS TWO NOVEL POTENTIAL AGENTS AGAINST ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Cocito Carolina , Padilla Christopher C , Pisapia David J , Hertz Charli Ann J , Dahmane Nadia , Greenfield Jeffrey P 
Published: June 2024

Abstract

BACKGROUND
Adamantinomatous craniopharyngiomas (ACPs) are rare intracranial suprasellar tumors, primarily affecting pediatric population. ACPs are histologically benign but their location makes them highly debilitating and clinically challenging with no standard of care available. Mutations in exon 3 of the CTNNB1 gene, codifying for β-catenin, are pathognomonic hallmark of ACPs. Although several cell lines and patient-derived models have been sporadically described, no reproducible pre-clinical models are available for these tumors.

METHODS
Eight ACP patients underwent gross total resections and we were able to generate novel cell lines from four of them. The lines, named CBTP-77, CBTP-97, CBTP-101 and CBTP-119, grow consistently and have been passaged more than 15 times. Immunocytochemistry and RNA sequencing were performed, highlighting inter- and intra-line heterogeneity, typical of ACP tumors. To identify new therapeutic targets, High Throughput Drug Screening (HTDS) was performed on two lines.

RESULTS
β-catenin inhibitor tegatrabetan, FGFR inhibitor erdafitinib, and the proteasome inhibitor bortezomib resulted as top effective agents. In vitro validation of the three agents confirmed strong cytotoxicity and on target activity shown by downregulation of the WNT and PI3K/AKT/mTOR pathways. The limited CNS permeability of these agents, makes them great candidates for local intra-cystic delivery, as described for other therapeutic options for ACP.

CONCLUSIONS
Our study represents the first large scale screening for new therapeutic agents for ACP, highlighting the importance of establishing consistent cell lines and preclinical models for these rare and devastating tumors.
CP-10. DOES PRE-IRRADIATION GROSS TUMOR VOLUME PREDICT THE RISK OF PROGRESSION AFTER RADIATION THERAPY IN PEDIATRIC PATIENTS WITH ADAMANTINOMATOUS CRANIOPHARYNGIOMA?
Authors: Brooks Tamar , Gao Dexiang , Dorris Katie , Mirsky David M , Staulcup Susan , Prince Eric , Moskalenko Marina , Ignowski Elizabeth , Wandrey Narine , Fakhoury Kareem , Hankinson Todd C , Milgrom Sarah A 
Published: June 2024

Abstract

OBJECTIVE
In a cohort of patients who were treated with resection and adjuvant radiotherapy (RT) for adamantinomatous craniopharyngioma (ACP), we explored whether gross tumor volume (GTV) at the initiation of RT was associated with the risk of progressive disease (PD) following treatment.

METHODS
Pediatric and adolescent patients who received surgery and RT for ACP at a single institution from 1998-2021 were identified. Univariable Cox regression analyses (UVA) were performed to assess the association between pre-RT GTV and PD after RT. Multivariable analyses (MVA) were used to control for potential confounders. Two different endpoints were used to define PD. The first definition was based on radiographic tumor growth and the second definition was the requirement for an additional tumor-directed intervention following the completion of RT.

RESULTS
48 patients were eligible for inclusion. The median age at diagnosis was 7.9 years (range: 2.1-17.4). All patients were treated with surgery and RT with median dose of 52.2 Gy (range: 45-55.8 Gy) and median GTV of 9.86 cm3 (range 0.7-117.7 cm3). Upon follow-up, 8 patients experienced PD based on both definitions. Five-year EFS was 85.4% (95% CI: 74.1 -98.3%). On both UVA and MVA, GTV was significantly associated with a small increased likelihood of PD (HR 1.02, 95% CI 1.00 - 1.04, p=0.022). However, after exclusion of a single outlier with GTV of 117.7 cm3 prior to RT, a second analysis identified no significant association between GTV and PD (UVA: HR 1.03, p=0.4; MVA: HR 1.06, p=0.2).

CONCLUSIONS
For most patients with ACP, the GTV at the initiation of RT is not associated with the risk of PD. This finding suggests that aggressive tumor debulking for the purpose of improving the efficacy of RT may not be necessary. For giant ACPs, however, novel strategies may be necessary for tumor control.