bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-09. CNS EMBRYONAL TUMOUR WITHZNF532:NUTM1 FUSION: A RARE NEW CNS TUMOUR TYPE
Authors: Haberler Christine , Schned Hannah , Müllauer Leonhard , Schmook Maria , Sievers Philipp , Aldape Kenneth , Zied Abdullaev , von Hoff Katja , Johann Pascal , Gojo Johannes 
Published: June 2024

Abstract

BACKGROUND
Rare embryonal and sarcomatous CNS tumours represent a diagnostic and therapeutic challenge. In the latest WHO 2021 several new tumour types, defined by molecular alterations, have been introduced. Some of these tumours have molecular counterparts outside the CNS e.g. CNS tumour with BCOR alteration or CIC-altered sarcoma.We report a CNS tumour with unusual histological and molecular features.

METHODS/RESULTS
A 3-year-old boy presented with a 5x3 cm sized tumour in the left lateral ventricle, which was removed at an external institution. After treatment with 1 cycle carboplatin/etoposide the patient presented at our clinic with leptomeningeal dissemination across all CNS compartments. Therapy was switched to HIT-MED Guidance augmented by intraventricular therapy. Histology showed a highly cellular tumour composed of small uniform cells with round nuclei, distinct nucleoli and a scant cytoplasm. The cells were arranged sheet-like without discernible background. Mitotic figures were conspicuous. Immunohistochemically, expression of Olig2, Chromogranin A, NCAM, BCOR and EGFR was present; synaptophysin and SOX10 were positive in a fraction of cells. DNA methylation profiling using the DKFZ and the Bethesda CNS tumour classifier did not match with any methylation class. Archer FUSIONPlex panel revealed a ZNF532::NUTM1 fusion, which was confirmed by RNA sequencing, leading to the diagnosis of a CNS embryonal tumour NEC with ZNF532::NUTM1 fusion.

CONCLUSIONS
NUTM1 fusion oncogenes, including among other fusion partners ZNF532, are drivers of aggressive NUT carcinomas. Furthermore, NUTM1 can be a fusion partner in CIC-rearranged sarcoma. The present case neither qualified as carcinoma nor sarcoma. As no clear response was evident after 3 cycles of HIT-MED Guidance therapy was switched to the Scandinavian Sarcoma Protocol. A similar case showing embryonal morphology has been recently reported (PMID 37203791). In conclusion, the spectrum of NUTM1-rearranged tumours is expanding and rare unclassifiable CNS embryonal tumours should be checked for NUTM1 immunopositivity/rearrangement.
LMIC-10. GLOBAL MAPPING OF CLINICAL TRIALS FOR CHILDREN WITH CNS TUMORS
Authors: Mikkelsen Margit , Sotelo Catrian , Kelley Mackenzie , Edwards Michael , Moreira Daniel 
Published: June 2024

Abstract

BACKGROUND
While there has been an international call to increase access to pediatric oncology clinical trials, the current landscape of global clinical trials for pediatric central nervous system (CNS) tumors has not been described. We sought to analyze the availability of clinical trials available for children with CNS tumors worldwide.

METHODS
Clinical trials were included if they were interventional studies registered in International Clinical Trials Registry Platform (ICTRP) that included pediatric patients (≤17 years old) with a CNS tumor. PubMed and Google Scholar were used to identify peer-reviewed manuscripts describing the results of identified trials.

RESULTS
From 114,414 oncology trials, 322 studies met inclusion criteria. Geographically, 307 (95%) studies were sponsored by and conducted in high-income countries (HICs), while 15 studies (4.7%) were sponsored by and conducted in middle-income countries (MICs). No studies were registered in or accrued from low-income countries. Studies were mostly sponsored in the United States (244, 76%), United Kingdom (20, 6.2%), or France (13, 4.0%). Trials were mostly sponsored by individual institutions (168, 52%), followed by governmental organizations (100, 31%), collaborative groups (36, 11%) and pharmaceutical companies (18, 5.5%). Study characteristics differed with income status, with HICs registering mostly clinical trials for cancer-directed treatment (261, 85%) and MICs registering later phase supportive care-based or diagnostic trials (9, 60%). Of the studies included, 132 (43%) were published. There were similar rates of publishing results in HIC and MICs. Discussion: Low- and middle-income countries are under-represented in the global clinical research landscape of pediatric CNS tumors. Furthermore, these data describe the urgent needs to invest in clinical research infrastructure in LMICs and to foster collaborations that include LMICs as a critical step in achieving equity in global pediatric cancer care.
LMIC-12. INFANT-TYPE HEMISPHERIC GLIOMA: CAN IT BE EFFECTIVELY MANAGED IN AN UPPER-MIDDLE-INCOME COUNTRY?
Authors: Dassi Natália , Balsanelli Julia D , Toledo Silvia R C , Gamba Francine T , Alves Maria T S , Cavalheiro Sergio , Dastoli Patricia A , Costa Marcos D , Silva Frederico A , Silva Nasjla S , Cappellano Andrea M 
Published: June 2024

Abstract

BACKGROUND
Infant-type hemispheric glioma (IHGs) is a rare congenital tumor and a newly defined entity in the 2021 WHO classification for central nervous system tumors. It harbors, in mostly cases, a tyrosine kinase receptor rearrangement in NTRK family, ALK, ROS1 and MET. The aim of this study is to describe the demographic characteristics, treatment, and outcomes of a cohort of pediatric patients with IHGs in one single institution.

METHODS
A retrospective study was performed between 2012-2023. Overall survival (OS) was measured from diagnosis to date of death or last follow-up. The Kaplan–Meier method was used for survival analysis.

RESULTS
Fourteen patients were included. Median age was 4.4 months (range 0.1- 37months). All patients underwent neurosurgical resections, with a median of 2 (range 1-6). Eight patients performed molecular analyses showing three ALK, two NTRK, two ROS and one MET rearrangement. Twelve patients received chemotherapy-lines, four of them more than one schema, with a median of 3 (range 2-5). Three patients were submitted to focal radiotherapy after 3 years of age and three received target therapies (crizotinib/ alectinib, lolartinib and repotrectinib). In a median follow-up of 46.9 months (2-125months), the OS in 5/10 years was 73.9% and 55.4%, respectively. Four patients died, one due to neurosurgical complications at diagnosis, one from refractory seizure 47 months after diagnosis with no evidence of disease, and two due disease progression with eight and 74 months after initial diagnosis, the last one despite 2-lines of target therapy.

CONCLUSION
Our series reveals acceptable and encouraging survival rates, demonstrating that not only new molecular discoveries but also optimal multidisciplinary treatment makes a difference in survival of patients with IHG even in countries with limited resources. However, access to targeted therapy remains an obstacle to be overcome for the optimal management of these patients.
LMIC-19. A RETROSPECTIVE ANALYSIS OF PEDIATRIC RECURRENT PINEOBLASTOMA IN BEIJING
Authors: Li Miao , Sun Yanling , Zhang Zhen , Wu Wanshui , Sun Liming 
Published: June 2024

Abstract

OBJECTIVE
To explore the clinical characteristics of pediatric recurrent pineoblastoma in Beijing.

METHODS
Eighteen patients with newly diagnosed pineoblastoma were admitted to Beijing Shijitan Hospital between January 2014 and December 2022. The clinical data were retrospectively analyzed.

RESULTS
Among the 18 patients (M/F=8:1), all were treated with surgery, and both radiotherapy and chemotherapy were administered. Nine patients experienced recurrence, and 2 patients died at last follow-up. The Median follow-up time were 56 months. The 5-year progression-free survival (PFS) and 5-year overall survival (OS) were (42.0±13.1) %, and (88.1±7.9) %, respectively. Among the 9 recurrent patients, one was &lt; 3 years, and 8 cases ≥ 3 years. One girl and 8 boys relapsed; 7 cases were M0 and 2 with metastases at diagnosis; 7 cases were GTR; Two cases experienced recurrence within one year (10 months each), and one died. The other 7 patients relapsed after one year, the median time to first relapse were 24.0 (range: 10.0~49.0)months. The sex, age group, metastases at diagnosis, GTR or not, recurrent sites were not significantly affects PFS. Although the 9 recurrent patients received both cerebral and spinal irradiation and chemotherapy followed by surgery, the different order of chemotherapy or radiotherapy first were significantly affected the duration of remission. The median time before the first relapse after surgery was longer in those who treated under the order of craniospinal irradiation followed by chemotherapy than those of the inverse order (29m vs 13m, χ2=6.528, P=0.011). In addition, one case with germline mutation of Dicer1, experienced recurrences more than 3 times although received second surgery and second radiotherapy, and multiple cycles of chemotherapy in our center, which indicates poorer outcome.

CONCLUSION
Pineoblastoma is rare and prone to relapse, the order of chemotherapy first may have shorter remission time before the first recurrence after surgery (P&lt; 0.05).
MODL-07. BUILDING BETTER MODELS OF BRAIN TUMOURS TO ADVANCE PATIENT TREATMENT WITH MINIMAL SIDE EFFECTS
Authors: Gkotsi Danai Stella , Forder-Denham Isabelle , Ritzmann Timothy A , Ramage Judith , Kerr Ian D , Jackson Andrew , Mata Alvaro , Coyle Beth 
Published: June 2024

Abstract

BACKGROUND
Paediatric brain tumours pose a formidable challenge in oncology, necessitating innovative approaches to bridge the gap between molecular understanding and therapeutic efficacy. Current preclinical models lack fidelity in capturing the dynamic interplay between tumour cells and their microenvironment, hindering translation of research findings into clinical practice.

METHODS
We are developing advanced three-dimensional (3D) models of paediatric brain tumours, integrating crucial components of the tumour microenvironment. Leveraging self-assembling peptide amphiphiles (PAs), we are constructing subgroup-specific PA-ECM-Immuno models mimicking brain stiffness, ECM composition, immune cell interactions, and oxygen levels. Spatial transcriptomics and multiplex immunohistochemistry are being employed to elucidate tumour-microenvironment interactions.

RESULTS
Building upon our successes in modelling brain tumour growth and behaviour, as well as other types of tumours (the Mata lab has previously successfully established PA-ECM models of prostate and ovarian cancer), our approach demonstrates feasibi lity in incorporating immune cells and subgroup-specific ECM components into PA-ECM matrices. These models provide insight into dynamic interactions driving tumour progression, facilitating identification of key pathways and potential therapeutic targets.

CONCLUSIONS
Our approach represents a novel paradigm in paediatric neuro-oncology research, aiming to establish clinically relevant 3D models faithfully recapitulating intricate tumour-microenvironment interactions. By elucidating mechanisms of tumour progression and employing spatial transcriptomics and multiplex immunohistochemistry, our tailored models will enable the identification of precision therapies with enhanced efficacy and reduced off-target effects. Collaborative efforts through our multidisciplinary approach are poised to advance the field towards personalised treatments and improved outcomes for paediatric brain tumour patients.
MODL-14. TARGETING GL1/GL2-DNMT1-UHRF1 EPIGENETIC COMPLEX DISRUPTION VIA BET INHIBITION IMPAIRS SHH MB DEVELOPMENT
Authors: Jangde Nitish , Wynn Daniel , Egan Isabelle , Robbins David , Ayad Nagi 
Published: June 2024

Abstract

BACKGROUND
Sonic Hedgehog Medulloblastoma (SHH MB) shares 30% among all molecular subtypes of medulloblastomas (MBs). Constitutive activation of SHH signaling in the cerebellum’s granular cell precursors (GCPs) is critical for this MB development. When SHH receptor PATCHED-1 (PTCH1) is mutated, stimulation of this receptor by SHH ligand binding leads to derepression of heterotrimeric GTP-binding protein–coupled receptor Smoothened (SMO) eventually altering the activity, location, and stability of the three downstream glioma associated oncogene (GLI) family members: GLI1, GLI2, and GLI3. GLI1 and GLI2 mostly function as transcriptional activators, while GLI3 mainly plays a repressor role. The bromodomain and extra-terminal domain (BET) family of proteins comprises four conserved members (Brd2, Brd3, Brd4, and Brdt), which are critical regulators of GLI1 and GLI2-mediated transcription.

METHODS
In the present study, we pharmacologically inhibited BETs with a previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, discovered by our lab. We treated human SHH MB cells (ONS76 cells) in vitro and ex vivo in mouse SHH MB cells (from Ptch1 conditional knockout mice) with minimum effective concentrations of these inhibitors. We screened for GLI1/GLI2-DNMT1-UHRF1 epigenetic complex components expressions by immunoblotting and assessed the effectiveness of inhibiting their interactions by performing PLA assays.

RESULTS
In this study, we show that pharmacological inhibition of BETs leads to attenuated GLI1 and GLI2 levels. This GLI1 and GLI2 inhibition eventually disrupts the previously reported GL1/GL2, DNMT1-UHRF1 epigenetic complex, which is crucial for SHH MB development. A previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, synthesized and characterized by our lab can inhibit BETs. This could be a potential therapeutic approach targeting GLI-associated epigenetic complexes to treat SHH medulloblastoma.
STEM-01. DEVELOPMENT OF A HUMAN-SPECIFIC 3DIN VITRO PAEDIATRIC CEREBELLAR TUMOUR MODEL USING DECELLULARISED BRAIN AUTOPSY TISSUE
Authors: McCrorie Phoebe , Porter Harry , Diksin Mohammed , Moloney Cara , Grundy Richard , Rahman Ruman 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) and Atypical Teratoid/ Rhabdoid Tumours (ATRT) represent paediatric cerebellar tumours with a dismal prognosis. For ATRT in particular, 5-year survival remains at less than 32%. We have developed a 3D in vitro model termed ‘tumoursphere matrix’ which recapitulates in vivo crosstalk between tumour and reactive brain.

METHODS AND RESULTS
We co-cultured D283 (Group 3-MYC amplified MB) and BT12 (ATRT-MYC) cells with primary human cerebellar astrocytes within a PEGDA hydrogel containing decellularised cerebellar extracellular matrix (ECM) derived from non-disease human autopsy brain. Cerebellar ECM was extensively characterised, showing a significant reduction in cellular material whilst retaining ECM ligands. Reduction of DNA content to 174 ng/mg was corroborated by an absence of nuclei in immunohistochemical staining. Colorimetric assays indicated collagen and glycosaminoglycan retention in decellularised ECM, and Immunofluorescence confirmed retention of fibronectin, laminin and hyaluronic acid. Detection of all ECM ligands was cross-validated by Orbitrap-Secondary Ion Mass Spectrometry. A solubilised ECM/PEGDA hydrogel was used to coat an AggreWell™ plate. Primary human cerebellar astrocytes, D283 and BT12 cells were cultured as spheroids within the ECM/PEGDA hydrogel for 7 days with no significant decrease in cellular viability. Cytokine and Human Matrix Metalloproteinase (MMP) Antibody Arrays showed cytokine and MMP expression in all three cell lines was retained in the presence of ECM material. Furthermore, D283 and BT12 cells were co-cultured with primary astrocytes for 7 days prior to separation using fluorescence activated cell sorting to generate individual cell populations.

CONCLUSIONS
We have developed a 3D in vitro model which can co-culture cells for over 7 days, whilst recapitulating the in vivo tumour environment. RNA sequencing is currently in progress to identify differentially expressed genes in cerebellar tumour cells upon astrocytic and brain ECM crosstalk. We hypothesise that biochemical signalling underlying this communication will reveal putative therapeutic vulnerabilities.
STEM-06. THE ROLE OF SHH SIGNALING PATHWAY IN RETINOBLASTOMA INITIATION AND PROGRESSION
Authors: Liu Xiao , Murad Najiba , Pei Yanxin , Micklye McKayla Bridgette 
Published: June 2024

Abstract

BACKGROUND
Retinoblastoma is a rare childhood cancer of the retina that shows the biallelic loss of RB1 in nearly 95% of cases. It was reported that SHH pathway proteins, such as SHH, GLI1, and GLI2, are aberrantly high in human retinoblastoma, and high GLI2 expression is associated with aggressive clinicopathological features. Thus, we assessed whether activation of SHH pathway by overexpression of Gli2 or SMO induces the initiation of retinoblastoma.

METHODS
We generated a Cre-activated, Doxycycline (Dox)-controlled transgenic model to induce SMO or Gli2 expression in developing retina. In this transgenic mouse, expression of Smo or Gli2A is under the control of TRE, which permits temporal and spatial expression of Smo or Gli2A by administering/withdrawing doxycycline (DOX).

RESULTS
We fed the triple transgenic mice (Chx10-Cre/R26-LSL-rtTA/tetO-Smo or Chx10-Cre/R26-LSL-rtTA/tetO-Gli2A starting from E0 or P5. Our studies demonstrated that control littermates (Cre-) did not show any abnormalities, while mice with triple transgenes developed tumors in the bilateral eyes with 100% morbidity. The animals showed symptoms of leukocoria at P0-P3 or P25-p30 if the oncogenes were initiated at E0 or P5 respectively. The tumor cells were highly proliferative and expressed retina progenitor cell specific marker of Sox2, showing aberrant expression of pRB, CDK4/6, and CCND1.

CONCLUSIONS
Our results demonstrate that overexpressing Smo or Gli2 in Chx10+ cells induce rapid tumor formation in mouse retina. In future study, we plan to (i) investigate the impact of Shh pathway activation in RPCs on RB tumorigenesis within the context of Rb1 loss; (ii) define the molecular mechanisms underlying tumor initiation and progression; and (iii) evaluate whether targeting SHH pathway prevents or delays tumor initiation and progression using our Gli2-driven mouse model and patient-derived xenografts.
Dual role of proliferating cell nuclear antigen monoubiquitination in facilitating Fanconi anemia-mediated interstrand crosslink repair
Authors: Shah Ronak , Aslam Muhammad Assad , Spanjaard Aldo , de Groot Daniel , Zürcher Lisa M , Altelaar Maarten , Hoekman Liesbeth , Pritchard Colin E J , Pilzecker Bas , van den Berk Paul C M , Jacobs Heinz 
Published: June 2024

Abstract
The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated by REV1 or site-specific monoubiquitination of proliferating cell nuclear antigen (PCNA) (PCNA-Ub) at lysine 164 (K164). A PcnaK164R/K164R but not Rev1−/− mutation renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair (1, 2), though the decision making between those remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair, we intercrossed PcnaK164R/+; Fancg−/+ mice. A combined mutation (PcnaK164R/K164R; Fancg−/−) was found embryonically lethal. RNA-seq of primary double-mutant (DM) mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints. To exclude stress-induced confounders, we utilized a Trp53 knock-down to obtain a model to study ICL repair in depth. Regarding ICL-induced cell toxicity, cell cycle arrest, and replication fork progression, single-mutant and DM MEFs were found equally sensitive, establishing PCNA-Ub to be critical for FA-ICL repair. Immunoprecipitation and spectrometry-based analysis revealed an unknown role of PCNA-Ub in excluding mismatch recognition complex MSH2/MSH6 from being recruited to ICLs. In conclusion, our results uncovered a dual function of PCNA-Ub in ICL repair, i.e. exclude MSH2/MSH6 recruitment to channel the ICL toward canonical FA repair, in addition to its established role in coordinating TLS opposite the unhooked ICL.
Systematic discrepancies in the delivery of political ads on Facebook and Instagram
Authors: Bär Dominik , Pierri Francesco , De Francisci Morales Gianmarco , Feuerriegel Stefan 
Published: June 2024

Abstract
Political advertising on social media has become a central element in election campaigns. However, granular information about political advertising on social media was previously unavailable, thus raising concerns regarding fairness, accountability, and transparency in the electoral process. In this article, we analyze targeted political advertising on social media via a unique, large-scale dataset of over 80,000 political ads from Meta during the 2021 German federal election, with more than 1.1 billion impressions. For each political ad, our dataset records granular information about targeting strategies, spending, and actual impressions. We then study (i) the prevalence of targeted ads across the political spectrum; (ii) the discrepancies between targeted and actual audiences due to algorithmic ad delivery; and (iii) which targeting strategies on social media attain a wide reach at low cost. We find that targeted ads are prevalent across the entire political spectrum. Moreover, there are considerable discrepancies between targeted and actual audiences, and systematic differences in the reach of political ads (in impressions-per-EUR) among parties, where the algorithm favor ads from populists over others.
Consequences of gene editing of PRLR on thermotolerance, growth, and male reproduction in cattle
Authors: Cuellar Camila J. , Amaral Thiago F. , Rodriguez‐Villamil Paula , Ongaratto F. , Martinez D. Onan , Labrecque Rémi , Losano João D. de Agostini , Estrada‐Cortés Eliab , Bostrom Jonathan R. , Martins Kyra , Rae D. Owen , Block Jeremy , Hoorn Quinn A. , Daigneault Bradford W. , Merriam Jonathan , Lohuis Michael , Dikmen Serdal , Bittar João H. J. , Maia Tatiane S. , Carlson Daniel F. , Larson Sabreena , Sonstegard Tad S. , Hansen Peter J. 
Published: June 2024

AbstractGlobal warming is a major challenge to the sustainable and humane production of food because of the increased risk of livestock to heat stress. Here, the example of the prolactin receptor (PRLR) gene is used to demonstrate how gene editing can increase the resistance of cattle to heat stress by the introduction of mutations conferring thermotolerance. Several cattle populations in South and Central America possess natural mutations in PRLR that result in affected animals having short hair and being thermotolerant. CRISPR/Cas9 technology was used to introduce variants of PRLR in two thermosensitive breeds of cattle – Angus and Jersey. Gene‐edited animals exhibited superior ability to regulate vaginal temperature (heifers) and rectal temperature (bulls) compared to animals that were not gene‐edited. Moreover, gene‐edited animals exhibited superior growth characteristics and had larger scrotal circumference. There was no evidence for deleterious effects of the mutation on carcass characteristics or male reproductive function. These results indicate the potential for reducing heat stress in relevant environments to enhance cattle productivity.