bluuebunny/crossref_metadata_2025 huggingface dataset:
SURG-14. Value of the Classification of Intraoperative Adverse Events (ClassIntra) for Resection of CNS Neoplasms in Pediatric and Adolescent Patients
Authors: Drexler Richard , Fritzsche Friederike , Ricklefs Franz , Kammler Gertrud , Dohrmann Thorsten , Nitzschke Rainer , Westphal Manfred , Dührsen Lasse
Published: June 2022

OBJECTIVE: Outcome measuring is increasingly important in neurosurgery. Recently, a classification for assessing Intraoperative adverse events (iAE) was introduced (ClassIntra). We aimed to analyze the reliability of the ClassIntra to reflect Intraoperative complications and the potential to predict the outcome of pediatric and adolescent patients who underwent resection of CNS neoplasms. METHODS: A prospective study between 01 July and 31 December 2021 was conducted. The ClassIntra grade for each tumor resection was evaluated at sign-out (Grade 0 to V). Postoperative complications were graded after Clavien-Dindo and Comprehensive Complication Index (CCI). Neurological status was assessed prior surgery and at discharge using Lansky Index, NIHSS, NANO, GCS, and mRS. RESULTS: 21 pediatric and adolescent patients who underwent resection of CNS neoplasms were included. Of these, 8 (38.1%) were female with a mean (SD) age of 9.9 (5.2) years. During 13 (61.9%) resection an iAE was noted, of which 11 (52.4%) were classified as ClassIntra I and 2 (9.5%) as ClassIntra II. The majority (66.7%) underwent surgery for infratentorial pathology, whereas 4 (19.0%) had a supratentorial and 3 (14.3%) a spinal pathology. Preoperative characteristics did not correlate with the severity of ClassIntra. In patients without an iAE, a gross total resection was achieved more frequently (p=0.048). Focusing on postoperative outcome revealed a higher severity of cumulative complications as presented by the CCI (10.4 versus 40.5), longer hospital stay (p=0.04), and higher 30-day readmission rate (p<0.01) in patients with an iAE. However, the neurological outcome and time to begin of adjuvant treatment did not correlate with the ClassIntra. CONCLUSION: Findings of this study suggest that the ClassIntra is sensitive for assessing iAEs and sufficient to identify cases with a higher risk for developing postoperative complications after resection of CNS neoplasms in pediatric and adolescent patients, but cannot predict a possible neurological deterioration.
OTHR-01. Papillary tumor of pineal region rare pediatric CNS tumor: case series treated in King Fahad Medical City KFMC
Authors: Ali Mobark Nahla , AlHarbi Musa , Alotabi Fahad , Alshoumer Azhar , Alsadi AbdulAziz , AlNaqib Zaid G , Shakweer Wafa Al , Balbaid Ali O , Abedalthagafi Malak
Published: June 2022

Clinical behaviors, prognosis, and appropriate treatments of PTPR are not fully defined due to the rarity of these tumors. At diagnosis, PTPR may present with various clinical symptoms with obstructive hydrocephalus, as well as neurological signs including Parinaud’s syndrome. Radiological assessment of pineal region lesions is challenging with a wide range of potential differential diagnoses. PTPR typically presents as a heterogeneous, well circumscribed mass in the pineal region. we report 3 female pediatric cases of PTPR treated in our institution. Histological and immunohistochemical diagnosis was confirmed by analysis of genome-wide DNA methylation profiles. the first case presenting with spinal leptomeningeal dissemination with excellent tumor control with radiation therapy alone. The second patient had aggressive course with recurrent local tumor growth despite radiation therapy and 0repeated surgical resections and she responded well to Pineoblastoma like intensive chemotherapy6 repeats of alternating 4-week cycles A&B : Cycle A: Cisplatin 90 mg/m2/day, day 1 of a & oral Etoposide 35 mg/m2/day P.O. days 1-21 . Cycle B: Cyclophosphamide 1 g/m2/day, days 1 and 2, Vincristine 1.5 mg/m2, days 1, 8 . While the third patient after first near gross total surgical resection with no recurrence for 18 months without adjuvant therapy then she had local recurrence which was salvaged by second complete resection and focal radiation The proper therapeutic strategy for PTPR is not clearer and the clinical behavior of PTPRs can be compared to that of ependymoma with complete resection is the mainstay of treatment and we recommend that adjuvant therapies like radiation with or without or chemotherapy should be considered when complete surgical resection is not feasible. This case series expands on the available reports on the clinical presentations of PTPR and provides important information on the responses to different treatments modalities
OTHR-25 Germline Mutations in Pediatric Brain Tumor
Authors: Li Shaoqun , Lai Mingyao , Cai Linbo
Published: June 2022

BACKGROUND: The exploration of germline mutations in pediatric brain tumor is helpful to improve the understanding of tumor genesis, guide the treatment, and provide genetic counseling for patients and their families. METHODS: In this study, children with primary brain tumor aged ≤18 years old in Guangdong Sanjiu Brain Hospital were enrolled．Tumor tissue or cerebrospinal fluid (CSF) next-generation sequencing (NGS) tests were required for all included patients. The genetic mutations in these children were analyzed and patients with germline mutations were screened. RESULTS: 135 pediatric patients with NGS detection were included in this patients. 63 patients were medulloblastoma, 54 were glioma. The rest were 5 ependymoma, 2other embryonal tumors, 2 pineoblastoma, 2 germ cell tumors, 1 pituitary adenoma, 1 neuroepithelial tumor, 1 Schwannoma, 1 neuronal tumor, 1 craniopharyngioma and 1 Rosai-Dorfman disease. NGS was performed on tissues of 122 patients and CSF of 13 patients. 7 patients underwent whole exome sequencing and the remaining 115 patients underwent panel detection. 6.67% (9/135) patients took germline mutations, which included 4 gliomas, 3 medulloblastomas, 1 schwannoma and 1 ependymoma. The rate of germline mutations were 7.41% (4/54) and 4.76% (3/63) in gliomas and medulloblastoma, respectively. The germinal mutations included TP53 missense mutation, BLM nonsense mutation, MSH2 nonsense mutation, MSH2 frameshift mutation, SUFU frameshift mutation, FANCI frameshift mutation, SBDS splicing site mutation, NF2 nonsense mutation and DIS3L2 nonsense mutation. These mutations are closely related to with Ligemeni syndrome, Bloom syndrome, Lynch syndrome, nevus basal cell carcinoma syndrome, Fanconi anemia, Shwachman-Diamond syndrome, neurofibromatosis type II and Perlman syndrome, respectively. 2 glioma patients had a family history of cancer. CONCLUSION: Pediatric patients with glioma, medulloblastoma, schwannoma and ependymoma are easily harboring germline mutations. For these patients, a detailed genetic history of family members is required and genetic counseling is recommended.
OTHR-42. Missing data tolerant integration of proteomic datasets enables the identification and characterization of brain cancer subtypes
Authors: Voss Hannah , Godbole Shweta , Schlumbohm Simon , Dottermusch Matthias , Schuhmann Yannis , Neumann Philipp , Schlüter Hartmut , Schüller Ulrich , Peng Bojia , Barwikowski Philip , Krisp Christoph , Neumann Julia E
Published: June 2022

Investigating the proteome can add a significant layer of information to manifold existing methylation, mutation, and transcriptome data on brain tumors as proteins represent the pharmacologically addressable phenotype of a disease. Small cohorts limit the usability and validity of statistical methods, and variable technical setups and high numbers of missing values make data integration from public sources challenging. Using a newly developed framework being able to reduce batch effects without the need for data reduction or missing value imputation, we show –based on in-house and publicly available datasets- successful integration of proteomic data across different tissue types, quantification platforms, and technical setups. Exemplarily, data of a Sonic hedgehog (Shh) medulloblastoma mouse model were analyzed, showing efficient data integration independent of tissue preservation strategy or batch. We further integrated batches of publicly available data of human brain tumors, confirming proposed proteomic cancer subtypes correlating with clinical features. We show that, missing value tolerant reduction of technical variances may be helpful to identify biomarkers, proteomic signatures, and altered pathways characteristic for molecular brain cancer subtypes.
OTHR-46. Single institution experience using molecular analysis of pediatric CNS tumors
Authors: Bendel Anne , Skrypek Mary , Pond Dinel , Olson Damon , Schultz Kris Ann , Roiko Samuel
Published: June 2022

Molecular analysis of pediatric CNS tumors helps confirm the diagnosis, but can also guide treatment by identifying prognostic factors allowing for treatment stratification, and by unveiling active signaling pathways which can be targeted. This report is a retrospective review of the molecular analysis performed on all CNS tumors biopsied or resected at Children’s Minnesota over the last 3 years to evaluate our current practices. From 2019-2021, 118 patients with newly diagnosed CNS tumors underwent surgery followed by molecular assessment (14 IHC/FISH, 85 NGS, 7 methylation profiling) on 100% of medulloblastoma, other embryonal tumors, and schwannoma; 90% of ependymoma; 88% of HGG; 71% of LGG/glioneuronal/neuronal tumors; and 50% of meningioma and craniopharygioma. MAPK pathway alterations were seen in 84% of LGG/glioneuronal/neuronal tumors, with KIAA1540-BRAF fusion seen exclusively in pilocytic astrocytoma and BRAFV600E alterations seen in diffuse LGG (75%), PLNTY and PXA. Frequent alterations seen in HGG included H3F3A-K27M, H3F3A-G34, TP53, PDGFRA, ATRX, CDKN2A/B. Common gene alterations in medulloblastoma included monosomy 6 (100%) and alteration of CTNNB1 (50%) in WNT subgroup; PTCH1 (75%) in SHH subgroup; MYC/MYCN gain (60%) or amplification (60%) in Non-WNT/SHH subgroup. Alterations in FOXR2 in CNS neuroblastoma, SMARCB1 in ATRT and C19MC in ETMR confirmed these diagnoses. Supratentorial ependymoma showed ZFTQ-RELA fusion (100%) and infratentorial ependymoma showed chromosomal copy number changes including 1q gain (40%). Meningiomas showed deletion of NF2 and SMARCB1 and craniopharyngioma had alterations in CTNNB1. Molecular analysis confirmed the diagnosis in 23% of tumors, aided with targeted treatment in 20% of patients (82% of HGG, 9% of LGG, 13% of medulloblastomas) and allowed for risk-adapted treatment in 93% of medulloblastomas. These findings indicate that identification of pathogenic variants in CNS tumors aids in the diagnosis and treatment of pediatric CNS tumors and should be considered standard practice.
LINC-11. Intrathecal methotrexate in a young child with medulloblastoma with extensive nodularity. An alternative to intra-ventricular route in Low and Middle Income Countries?
Authors: Leal-Cavazos Carlos , Arenas-Ruiz Jose , Vidal-Gutierrez Oscar
Published: June 2022

BACKGROUND: In places where determination of molecular subgrouping of Medulloblastoma is not available, histology remains standard for risk stratification and treatment. Young children with medulloblastoma treated with craniospinal irradiation show a negative impact in neurocognitive functions, thus avoiding radiation in this specific population is encouraged. High dose chemotherapy and stem cell rescue have been internationally used as a strategy to spare radiation in infants and young children with Medulloblastoma. German HIT protocol (SKK) reported a PFS 85±8 % and good cognitive outcome in patients with Desmoplastic Medulloblastoma treated with intra-ventricular (i.vtr.) methotrexate (MTX). SKK protocol includes 36 i.vtr. administrations of MTX through a subcutaneous reservoir. Complications related to the use of this kind of reservoir could be due to the lack of experienced staff. METHODS: We report a patient with localized Medulloblastoma with extensive nodullarity (MBEN) treated as per SKK using intrathecal route instead of i.vtr MTX. A 2.5 year old boy was diagnosed with MBEN, surgery was complete and no shunt was required. Spinal MRI and CSF cytology were negative. Patient received 3 cycles of SKK protocol and 2 cycles of modified SKK. During the first 3 cycles he received one dose of intrathecal MTX 8mg on weeks 1, 3, 5 and 7 (12 doses in all). Patient remains free of disease 2 years after chemotherapy completion and without signs of leukoencephalopathy on T2 weighted cranial MRI. DISCUSSION: Intrathecal administration of MTX is commonly used for the treatment of Acute Lymphoblastic Leukemia, the most common childhood cancer. Staff in Low and Middle Income Countries (LMIC) may be better trained for such procedure than using a ventricular access device. This strategy could be considered when using SKK protocol in selected young children with Demoplastic Medulloblastoma and MBEN in LMIC where centers with enough experience with ventricular access device placement and handling are scarce.
MODL-03. Establishment of intraventricular Shh inhibition as a therapeutic option for young patients with medulloblastoma
Authors: Kresbach Catena , Schoof Melanie , Holst Lea , Leven Tara , Yorgan Timur , Wrzeszcz Antonina , Rutkowski Stefan , Schüller Ulrich
Published: June 2022

The prognosis of pediatric medulloblastoma is still dissatisfying today and tumor survivors often suffer from severe treatment-related morbidities. This poses an urgent need for more efficient therapies. Shh medulloblastoma is characterized by mutations in the Sonic Hedgehog (Shh) pathway, providing an elegant way of targeted therapy. The small molecule Vismodegib allosterically inhibits Smoothened (SMO), an upstream activator of Shh, and shows promising anti-tumor effects against Shh medulloblastoma. Unfortunately, Vismodegib caused severe bone deformities in preclinical studies and clinical trials, preventing its systemic application in children. In a mouse model, we established an intraventricular therapy with Vismodegib combining the benefits of targeted drug delivery and minimal systemic side effects. We compare intraventricular, oral, and placebo treatment regarding effects on survival, tumor biology, and bone morphology.Math1-cre::Ptch1Fl/Fl mice show a homozygous loss of Ptch1 in Math1-positive cells, resulting in Shh pathway overactivation and development of Shh medulloblastomas. At postnatal day 11-13, Math1-cre::Ptch1Fl/Fl mice were randomized in four treatment arms: Group A (n=14) received intraventricular placebo, B (n=12) received 200 mg/kd/d oral Vismodegib, C (n=16) received 0.2 mg/kg/d intraventricular Vismodegib, and D (n=9) received 1.6 mg/kg/d intraventricular Vismodegib. Kaplan-Meier survival curves show a significant survival benefit of 1.6 mg/kg/d intraventricular Vismodegib over placebo (p=0.003). While all intraventricular treated animals develop proliferative tumors at end of observation, investigations at an early time point after completed treatment show promising anti-tumor effects with reduced or absent proliferation in the cerebellum compared to placebo. Bone histology and X-ray analysis of intraventricular treated mice show intact femoral and tibial growth plates, in contrast to orally treated mice that develop severe skeletal malformations. Based on these preliminary experimental results, we conclude that intraventricular application of a SMO-inhibitor might evolve as a promising new way of targeted treatment of Shh medulloblastoma in children.
MODL-14 Inhibition of cell cycle mechanisms to combat high-risk medulloblastoma
Authors: Bruckner Katharina , Mayr Lisa , Sickha Romana , Frederico Aniello , Madlener Sibylle , Gabler Lisa , Kirchhofer Dominik , Roessler Karl , Jäger Natalie , Berger Walter , Kool Marcel , Pfister Stefan M , Schueler Julia , Gojo Johannes , Lötsch-Gojo Daniela
Published: June 2022

Medulloblastoma (MB) is the most common embryonal brain tumor in children, characterized by a high level of heterogeneity within this entity. Four major molecular groups have been defined - WNT, Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4) - differing widely in genetic alterations and patient outcomes. Targeted treatment approaches are limited for high-risk MB including MYC-amplified G3, G4, or MYCN/GLI2-amplified SHH. Based on earlier studies describing the inhibition of cell cycle regulation as a therapeutic vulnerability in high-risk MB, we aimed to explore the efficacy and mode of action of approved CDK4/6 inhibitors in aggressive MB. First the in vitro sensitivity of pediatric G3 (n=5) MB cell models against palbociclib, ribociclib and abemaciclib was evaluated and compared to adult SHH (n=2) cells serving as MYC-negative controls. Abemaciclib most effectively reduced cell viability, exhibiting a mean IC50 value of 0.9 M in G3 compared to 2.1 M in SHH cells (p=0.007). Upon long-term exposure (7-10 days), again abemaciclib most potently decreased clonogenic survival already at 250nM in G3 MB cells. We observed a G1/S phase cell cycle arrest upon abemaciclib treatment and confirmed this by Western blot analyses, showing decreased Rb phosphorylation accompanied by reduced MAPK signaling. Interestingly, abemaciclib treatment distinctly reduced MYC protein and gene expression levels in MYC-amplified G3 cell models. In addition, exposure to abemaciclib decreased GLI2 and TERT mRNA levels, which was accompanied by induction of cellular senescence. Within the ITCC-P4 project, single mouse trials are currently being performed including abemaciclib treatment in orthotopic MB models. The detailed investigation of the precise mode of action in vitro and in vivo is ongoing. Summarizing, the CDK4/6 clinically approved inhibitor abemaciclib shows promising efficacy against high-risk MB in vitro.
MODL-30. Children’s Brain Tumor Network preclinical tumor models development and sharing platform: collaborative model empowering pediatric brain tumor discovery and global research.
Authors: Koptyra Mateusz , Baubet Valerie , Beale David , Patterson Luke , Biluck Ian , Hollawell Madison , Beck Christopher M , Sonawane Poonam , Griffin Crystal , Stern Allison , Madsen Peter , Foster Jessica , Lilly Jena , Mason Jennifer , Trooskin Gerri , Sullivan Catherine , Morgan Allison , Frenkel Beth , Lehmann Kaitlin , Lopez Lina , Nguyen Thinh , Agbodza Ena , Lopez-Gil Valeria , Helili Zeinab , Plisiewicz Alexa , Coleman Noel , Patton Tatiana , Stefankiewicz Stephanie , Arya Kamnaa , Velasco Ryan , Santi Mariarita , Viaene Angela , Storm Phillip B , Resnick Adam
Published: June 2022

Pediatric brain tumor preclinical field suffered for years from the lack of in vitro and in vivo models. With the explosion of novel therapy approaches for solid and brain tumors, including the immunotherapies it is essential to maximize the access to preclinical models for preclinical specificity, efficacy as well and safety. One of the many ways the Children’s Brain Tumor Network (CBTN) accelerates the pediatric brain tumor research and discovery is through support of the tumor model development program. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide provided free of charge. Here we present the resource platform with over 150 cell lines, organoids and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the tumor tissue use to generate a combination of cell line, organoids and/or xenograft models grown in animals. In recent years, consortium supported over 40 requests for cells lines used in basic biology and translational studies internationally. Current efforts focusing also on supporting large-scale data generation and testing through its collaborative model (Childhood Cancer Model Atlas, Procan, National Center for Advancing Translational Sciences) to maximize the molecular information available for each tumor model essential in preclinical screenings. The generated and returned to consortia data are bound with the deidentified patient clinical information and genomic data and freely available through Kid’s First Data, Cavatica and PedcBio portals. These efforts have already attracted interest from pharma stakeholders previously not observed in pediatric brain environment. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission to bring fast change to kids suffering from brain tumors.
RONC-10. Radiation-induced hypothyroidism in pediatric brain tumour survivors: radiation dose-volume predictors of its onset
Authors: Satragno Camilla , Verrico Antonio , Giannelli Flavio , Campora Sucheeta , Turazzi Marianna , Carmisciano Luca , Cavagnetto Francesca , Iorgi Natascia Di , Crocco Marco , Piccolo Gianluca , Casalini Emilio , Milanaccio Claudia , Garrè Maria Luisa , Belgioia Liliana , Barra Salvina
Published: June 2022

BACKGROUND: Central hypothyroidism is a well-known late effect of radiotherapy in children treated for brain tumours. AIM: To determine the risk of central hypothyroidism (CH) and the radiation dose-volume predictors of its onset. METHODS: We retrospectively analyzed 64 patients who received radiotherapy for brain tumours, with at least a 2-year-long serological follow-up, determined CH incidence and radiation predictive factors of its onset. To estimate the risk of CH according to the site of the tumour inside the central nervous system (CNS) we considered the sellar-suprasellar region, anterior cranial region, and others. For the same purpose, a further analysis was conducted comparing craniospinal radiotherapy (CSI) versus involved-field radiotherapy (IF-RT). Dose constraints for CH were determined using the Receiver Operating Characteristic to identify the pituitary mean dose cut-off and the probability of CH over time was assessed with the Cox model. RESULTS: 18 cases were excluded due to the presence of CH before RT; 17 of remaining 46 (37%) patients presented CH during follow-up: 14 of 17 (82%) patients received CSI, 3 (18%) IF-RT sellar-suprasellar region and anterior cranial region. A median dose higher than 30.5 Gy to the pituitary gland results in a 4-fold increased risk of central hypothyroidism (HR=3.9; 95% CI 1.1, 13.4; p=0.03). Almost 90% of events occurred within 5 years after treatment ended. 29 of 46 (63%) patients did not manifest CH and were in the "other regions”. However, 14 of these (48%) underwent CSI. CONCLUSIONS: Our data confirm the relationship between central hypothyroidism and mean pituitary radiation dose, and suggest a minimum of 5 years follow up in children brain tumor survivors. Tumours outside the sellar-suprasellar region, treated with radiotherapy, are not associated with CH onset. A significant association between CSI and risk of CH, highlighted with our analysis, warrants further investigations and a longer follow up
TBIO-08. The molecular basis for rational targeting of FGFR-driven growth and invasiveness in pediatric brain tumors
Authors: Migliavacca Jessica , Kumar Karthiga Santhana , Kopp Levi , Gries Alexandre , Yan Shen , Brunner Cyrill , Schuster Matthias , Jurt Simon , Moehle Kerstin , Zerbe Oliver , Schneider Gisbert , Grotzer Michael , Baumgartner Martin
Published: June 2022

The oncogenic activation of receptor tyrosine kinases (RTK) promotes growth, survival and dissemination in pediatric tumors including glioma, ependymoma and medulloblastoma (MB). Direct targeting of either the RTK or of downstream kinases can effectively block tumor promoting pathway functions. However, emergence of resistance is common. We hypothesized that alternative interference strategies that target protein-protein interactions (PPIs) instead of enzymatic activities could overcome the emergence of resistance. We characterized the molecular interactions downstream of the FGFR that regulate relevant growth and invasion-promoting mechanisms in MB cells, to identify potentially druggable PPIs. We found that the FRS2 protein is an essential up-stream effector of FGFR signaling towards invasiveness. Using a proteomics approach, we furthermore identified the Striatin 3 protein as a novel oncogenic effector of the FGFR pathway downstream of FRS2, as it integrates antagonistic growth and invasion signals downstream of FGFR. Mechanistically, Striatin 3 interacts with the Ser/Thr kinase MAP4K4, couples it to the protein phosphatase 2A, and thereby inactivates growth repressing activities of MAP4K4. In parallel, Striatin 3 enables MAP4K4-mediated phosphorylation of PKC-theta and VASP, which combined are necessary to promote tissue invasion. To selectively repress pro-invasive FGFR functions, we identified and functionally validated small molecule ligands of FRS2, that prevent FRS2 activation and downstream signaling. We demonstrate efficacy of these compounds in inhibiting invasion and growth promoting activities in vitro and in vivo, and identified potential off-target activities of the ligand using a proteome-wide interaction analysis. We propose inhibition of FRS2 by a small molecular PTB domain ligand as a strategy to repress FGF signaling in FGFR-driven tumors. The development of this ligand, and the de novo design of functional analogs thereof bear promise for further pre-clinical evaluation of these structures as anti-growth promoting and anti-metastatic therapeutics applicable to FGFR-driven tumors.
TBIO-11. The glutamine transporter and candidate diagnostic and therapeutic target SLC1A5 is associated with subtype-specific metabolic phenotypes and tumor prognosis in pediatric brain cancers
Authors: Kraya Adam , Jin Run , Zhao Chao , Familiar Ariana , Wellen Kathryn , Resnick Adam , Nabavizadeh Ali
Published: June 2022

Glutamine transporters play an important role in supporting increased tumor nutritional demands relative to non-cancerous cells, often through overexpression of the solute carrier (SLC) family of membrane transporters. Preclinical studies in adult cancers demonstrate that targeting glutamine addiction via SLC1A5 inhibition results in growth-inhibitory and tumoricidal effects. Given their relatively higher expression in cancer versus normal brain tissue, SLC transporters represent compelling targets for molecularly-targeted radiation and application of available prognostic amino-acid PET imaging probes. However, the role of SLC transporters in pediatric brain cancers has yet to be investigated. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes in ensemble survival models (Reactome: R-HSA-352230), we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Through transcriptome-based consensus clustering, we found that supratentorial, RELA fusion-positive ependymomas and sonic hedgehog-activated medulloblastomas were over-represented among clusters expressing higher levels of SLC1A5 (p = 3.38e-7 and p = 2.18-26, respectively). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 9.8e-4 and p = 0.032) and shorter PFS in LGG (p = 0.022). Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. Our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain cancers that warrant further investigation for molecularly-targeted treatment and amino-acid PET imaging.
INSP-05. Development of fast cortical rhythms in health and mental disease
Authors: Hanganu-Opatz Ileana
Published: June 2022

Synchronization of neuronal activity in fast oscillatory rhythms is a commonly observed feature in the adult cerebral cortex. While its exact functions are still a matter of debate, oscillatory activity in gamma frequency range (20-100 Hz) has been proposed to organize neuronal ensembles and to shape information processing in cortical networks. Gamma activity emerges from reciprocal interactions between excitatory and inhibitory neurons. A fine-tuned balance between excitatory drive and inhibitory feedback is mandatory for circuit function underlying cognitive performance, whereas imbalance between excitation and inhibition and resulting gamma disruption have been proposed to cause cognitive disabilities in psychiatric disorders. Despite extensive investigation of gamma activity in adult brain, its development and function early in life are still poorly understood. The talk will highlight recent experimental findings that uncover the mechanisms and role of fast oscillatory activity throughout development. We will uncover how different neuronal populations interact to generate gamma oscillations. Moreover, we will show that these early oscillations are necessary for the adult cognitive abilities. On the flip side, poorer mnemonic and social abilities that have been characterized in several psychiatric disorders, such as schizophrenia and autism, might result from developmental miswiring of the brain. Our data support this hypothesis by demonstrating that weaker fast oscillatory rhythms, sparser connectivity and lower communication are present in the core circuit of cognitive processing, including the prefrontal cortex, hippocampus and entorhinal cortex, in mouse models of these disorders. Together, these findings highlight the relevance of fast cortical rhythms early in life for the adult brain function.
INSP-09. Using genetically engineered mouse models and patient-derived orthotopic xenografts to develop new therapies for pediatric brain tumors.
Authors: Jonchere Barbara , Pribnow Allison , Morfouace Marie , Shelat Anang , Yu Jiyang , Rankovic Zoran , Gajjar Amar , Northcott Paul A , Robinson Giles W , Roussel Martine F
Published: June 2022

Medulloblastoma is the most common malignant pediatric brain tumor. Extensive molecular analysis by many groups around the world demonstrated four distinct subgroups, WNT, SHH, Group3 and Group4 that now all have been divided into 11 total subtypes, 8 for Grou3 and Group4 medulloblastoma. SHH with MYCN amplification and TP53 mutations and Group3 with MYC amplification are the most aggressive and the least curable with few to no therapeutic options for recurrent tumors. Over the last two decades, my group developed several murine models for Group3 with MYC and SHH with MYCN overexpression and p53 loss of function and patient-derived orthotopic xenografts that recapitulate the four tumor subgroups. In addition, several human Group3 medulloblastoma lines with MYC amplification have been established in 2D and 3D cultures. I will discuss how the development of these murine and human medulloblastoma models combined with high throughput drug screens and pre-clinical trials at St. Jude led to the identification of new therapies currently evaluated in clinical trials.
Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in supratentorial ependymoma
Authors: de Almeida Magalhães Taciani , Alencastro Veiga Cruzeiro Gustavo , Ribeiro de Sousa Graziella , Englinger Bernhard , Fernando Peinado Nagano Luis , Ancliffe Mathew , Rodrigues da Silva Keteryne , Jiang Li , Gojo Johannes , Cherry Liu Yulu , Carline Brooke , Kuchibhotla Mani , Pinto Saggioro Fabiano , Kazue Nagahashi Marie Suely , Mieko Oba-Shinjo Sueli , Andres Yunes José , Gomes de Paula Queiroz Rosane , Alberto Scrideli Carlos , Endersby Raelene , Filbin Mariella G , Silva Borges Kleiton , Salic Adrian , Gonzaga Tone Luiz , Valera Elvis Terci
Published: June 2022

Background

Supratentorial RELA fusion (ST-RELA) ependymomas (EPNs) are resistant tumors without an approved chemotherapeutic treatment. Unfortunately, the molecular mechanisms that lead to chemoresistance traits of ST-RELA remain elusive. The aim of this study was to assess RELA fusion-dependent signaling modules, specifically the role of the Hedgehog (Hh) pathway as a novel targetable vulnerability in ST-RELA.

Methods

Gene expression was analyzed in EPN from patient cohorts, by microarray, RNA-seq, qRT-PCR, and scRNA-seq. Inhibitors against Smoothened (SMO) (Sonidegib) and Aurora kinase A (AURKA) (Alisertib) were evaluated. Protein expression, primary cilia formation, and drug effects were assessed by immunoblot, immunofluorescence, and immunohistochemistry.

Results

Hh components were selectively overexpressed in EPNs induced by the RELA fusion. Single-cell analysis showed that the Hh signature was primarily confined to undifferentiated, stem-like cell subpopulations. Sonidegib exhibited potent growth-inhibitory effects on ST-RELA cells, suggesting a key role in active Hh signaling; importantly, the effect of Sonidegib was reversed by primary cilia loss. We, thus, tested the effect of AURKA inhibition by Alisertib, to induce cilia stabilization/reassembly. Strikingly, Alisertib rescued ciliogenesis and synergized with Sonidegib in killing ST-RELA cells. Using a xenograft model, we show that cilia loss is a mechanism for acquiring resistance to the inhibitory effect of Sonidegib. However, Alisertib fails to rescue cilia and highlights the need for other strategies to promote cilia reassembly, for treating ST-RELA tumors.

Conclusion

Our study reveals a crucial role for the Hh pathway in ST-RELA tumor growth, and suggests that rescue of primary cilia represents a vulnerability of the ST-RELA EPNs.
Acceptance of skin products in healthcare workers: an empirical investigation
Authors: Symanzik C , Skudlik C , John S M
Published: June 2022

Background

Healthcare workers (HCWs) are at high risk of developing hand eczema (HE). This can be exacerbated by hygiene measures related to the coronavirus disease (COVID-19). Using mild skin cleansers and emollients or moisturizers is central in the prevention of HE—especially with increased COVID-19 hygiene regimes.

Aims

This study aimed to assess parameters important for the acceptance of a skincare concept in HCWs.

Methods

In this proof-of-concept user trial, HCWs were provided ad libitum with hand wash oil and hand cream during the 6-month period, when occupationally acquired COVID-19 infections among HCWs were peaking in Germany and then surveyed about acceptance of the products using questionnaires.

Results

Of 135 HCWs, 115 (85%) responded. Skin tolerance of the hand wash oil and the hand cream was rated very good by 63% and 52% of the 115 participants, respectively. Of the 115 participants, 58% and 57% were very satisfied with the hand wash oil and the hand cream, respectively.

Conclusions

Acceptance of skin cleansing and skincare products in HCWs seems influenced by parameters such as self-assessed skin tolerance and self-reported overall satisfaction. It must be assumed that products are only used as recommended if they are well-accepted. Employers might survey employees about acceptance of products using the parameters identified to adjust concepts if necessary to sustainably contribute to the prevention of HE.
Experimentally reduced feather microbial loads improve reproductive performance in captive Zebra Finches
Authors: Burley Nancy Tyler , Azevedo Campos Felipe , Chien Emilie , Duarte Shauna , Kirshman Nathalie , Phan Alison Thuy Tien N , Wilson Kerianne M
Published: June 2022

We performed a laboratory experiment on caged, domesticated Australian Zebra Finches (Taeniopygia guttata castanotis) to assess the effects of antimicrobial treatment applied to birds’ plumage on the feather microbial loads of breeding pairs and their associated reproductive performance. Treatments included an experimental group that experienced frequent misting with a broad-spectrum antimicrobial, as well as 2 control groups. Microbial loads (colony forming units [CFUs]) sampled from the belly feathers of breeders were higher posthatching than prehatching, and experimental pairs had lower loads (one-half to one-third the CFU counts) than controls at all sampled breeding-cycle stages. Clutch size and hatching success did not differ among treatments, but experimental pairs fledged nearly 50% more offspring (mean = 3.5 per clutch) than controls (mean = 2.3 per clutch) due to experiencing much lower nestling mortality. Offspring development rate, as assessed by one metric, varied among treatments: beak color score sampled midway in the development of adult phenotype revealed that offspring of experimental pairs had more rapid development. Findings imply that experimentally reduced density of feather microbial loads on breeders decreased reproductive costs in the posthatch phase, resulting in increased offspring survival and condition. At the time offspring fledged, uropygial gland volume tended to be greater among breeders that had experienced antimicrobial application throughout the breeding cycle. These results are consistent with a growing literature showing that the feather microbiome contributes significantly to the evolution of avian life histories and behavior and indicate that Zebra Finches are a useful laboratory model for investigating in vivo effects of the feather microbiome on avian hosts.
Time to act: Early experience suggests stabilization care offers a feasible approach for adolescents after acute life-threatening opioid toxicity
Authors: Moore Eva M , Warshawski Tom , Jassemi Sara , Charles Grant , Vo Dzung X
Published: June 2022

British Columbia is the epicentre of the opioid crisis in North America. Illicit drug toxicity is now one of the top 3 causes of death for adolescents in British Columbia. Evidence informed treatment is available but adolescents rarely receive it. Non-fatal toxicity can provide an opportunity to intervene. Since 2018, paediatricians in British Columbia have been offering admission, involuntary if necessary, to adolescents presenting to hospital after a life-threatening illicit drug toxicity. This brief stay, termed “stabilization care,” offers medical and psychiatric assessments, withdrawal management and initiation of opioid agonist therapy and discharge planning. Hospital policies, procedures and protocols were revised to support the unique needs of this population. Early experience with 17 adolescents shows relatively high attachment to treatment services and opioid agonist treatment, suggesting that paediatric interdisciplinary teams, working strategically, can improve care for adolescents in the face of the opioid epidemic.
Phosphorylation of OsTGA5 by casein kinase II compromises its suppression of defense-related gene transcription in rice
Authors: Niu Yuqing , Huang Xiaoguang , He Zexue , Zhang Qingqing , Meng Han , Shi Hua , Feng Baomin , Zhou Yuanchang , Zhang Jianfu , Lu Guodong , Wang Zonghua , Zhang Wenli , Tang Dingzhong , Wang Mo
Published: June 2022

Plants manage the high cost of immunity activation by suppressing the expression of defense genes during normal growth and rapidly switching them on upon pathogen invasion. TGAs are key transcription factors controlling the expression of defense genes. However, how TGAs function, especially in monocot plants like rice with continuously high levels of endogenous salicylic acid (SA) remains elusive. In this study, we characterized the role of OsTGA5 as a negative regulator of rice resistance against blast fungus by transcriptionally repressing the expression of various defense-related genes. Moreover, OsTGA5 repressed PTI responses and the accumulation of endogenous SA. Importantly, we showed that the nucleus-localized casein kinase II (CK2) complex interacts with and phosphorylates OsTGA5 on Ser-32, which reduces the affinity of OsTGA5 for the JIOsPR10 promoter, thereby alleviating the repression of JIOsPR10 transcription and increasing rice resistance. Furthermore, the in vivo phosphorylation of OsTGA5 Ser-32 was enhanced by blast fungus infection. The CK2 α subunit, depending on its kinase activity, positively regulated rice defense against blast fungus. Taken together, our results provide a mechanism for the role of OsTGA5 in negatively regulating the transcription of defense-related genes in rice and the repressive switch imposed by nuclear CK2-mediated phosphorylation during blast fungus invasion.
Revisiting the origin and identity specification of the spikelet: A structural innovation in grasses (Poaceae)
Authors: Wang Yanli , Bi Xiaojing , Zhong Jinshun
Published: June 2022

Spikelets are highly specialized and short-lived branches and function as a constitutional unit of the complex grass inflorescences. A series of genetic, genomic, and developmental studies across different clades of the family have called for and permitted a synthesis on the regulation and evolution of spikelets, and hence inflorescence diversity. Here, we have revisited the identity specification of a spikelet, focusing on the diagnostic features of a spikelet from morphological, developmental, and molecular perspectives. Particularly, recent studies on a collection of barley (Hordeum vulgare L.), wheat (Triticum spp.), and rice (Oryza sativa L.) mutants have highlighted a set of transcription factors that are important in the control of spikelet identity and the patterning of floral parts of a spikelet. In addition, we have endeavored to clarify some puzzling issues on the (in)determinacy and modifications of spikelets over the course of evolution. Meanwhile, genomes of two sister taxa of the remaining grass species have again demonstrated the importance of genome duplication and subsequent gene losses on the evolution of spikelets. Accordingly, we argue that changes in the orthologs of spikelet-related genes could be critical for the development and evolution of the spikelet, an evolutionary innovation in the grass family. Likewise, the conceptual discussions on the regulation of a fundamental unit of compound inflorescences could be translated into other organismal groups where compound structures are similarly formed, permitting a comparative perspective on the control of biological complexity.
Friend or foe: Hybrid proline-rich proteins determine how plants respond to beneficial and pathogenic microbes
Authors: Banday Zeeshan Z , Cecchini Nicolás M , Speed DeQuantarius J , Scott Allison T , Parent Claire , Hu Ciara T , Filzen Rachael C , Agbo Elinam , Greenberg Jean T
Published: June 2022

Plant plastids generate signals, including some derived from lipids, that need to be mobilized to effect signaling. We used informatics to discover potential plastid membrane proteins involved in microbial responses in Arabidopsis (Arabidopsis thaliana). Among these are proteins co-regulated with the systemic immunity component AZELAIC ACID INDUCED 1, a hybrid proline-rich protein (HyPRP), and HyPRP superfamily members. HyPRPs have a transmembrane domain, a proline-rich region (PRR), and a lipid transfer protein domain. The precise subcellular location(s) and function(s) are unknown for most HyPRP family members. As predicted by informatics, a subset of HyPRPs has a pool of proteins that target plastid outer envelope membranes via a mechanism that requires the PRR. Additionally, two HyPRPs may be associated with thylakoid membranes. Most of the plastid- and nonplastid-localized family members also have pools that localize to the endoplasmic reticulum, plasma membrane, or plasmodesmata. HyPRPs with plastid pools regulate, positively or negatively, systemic immunity against the pathogen Pseudomonas syringae. HyPRPs also regulate the interaction with the plant growth-promoting rhizobacteria Pseudomonas simiae WCS417 in the roots to influence colonization, root system architecture, and/or biomass. Thus, HyPRPs have broad and distinct roles in immunity, development, and growth responses to microbes and reside at sites that may facilitate signal molecule transport.
Quality Improvement Content in Physical Therapist Education: A Scoping Review
Authors: Struessel Tamara S , Sleddens Nicole M , Jones Katherine J
Published: June 2022

Objective

The purpose of this study was to systematically review the literature regarding teaching quality improvement (QI) in physical therapist education based on the Institute of Medicine’s 6-element definition of QI. Educational activities in QI methods in physical therapist professional education curricula, their developmental stage, and their level of evaluation were described.

Methods

Keywords related to physical therapist students and QI educational activities were used to search studies indexed in PubMed, CINAHL, and ERIC published from 2004 through November 2020. This search yielded 118 studies. After applying inclusion and exclusion criteria, 13 studies were retained for full-text review, which was conducted independently by 2 reviewers. The University of Toronto framework was used to assess developmental stage, and Kirkpatrick’s taxonomy was used to assess the evaluation level of 4 retained studies.

Results

The scope of QI educational activities in the 4 retained studies was limited to 3 of the 6 elements of QI: identifying opportunities for improvement, designing and testing interventions, and identifying errors and hazards in care. None of the studies included educational activities to teach understanding and measuring quality of care. Three of the 4 studies spanned the first 2 stages of the University of Toronto framework (exposure and immersion); 1 study was limited to exposure. None of the studies assessed competence in QI methods. Evaluation of QI education was limited to Kirkpatrick levels 1 (reaction) or 2 (learning). None of the studies evaluated activities at level 3 (transfer of new behaviors) or level 4 (results).

Conclusion

Education in QI methods in professional physical therapist curricula may be limited in scope due to constraints in physical therapist education and the strategic objective of the profession to differentiate itself from other professions.

Impact

Entry-level physical therapists might not be educated to fully participate in interprofessional teams that use QI methods to continuously improve the quality of patient-centered care.
Anti-phosphatidylserine/prothrombin antibodies and thrombosis associate positively with HLA-DRB1*13 and negatively with HLA-DRB1*03 in SLE
Authors: Elbagir Sahwa , Diaz-Gallo Lina-Marcela , Grosso Giorgia , Zickert Agneta , Gunnarsson Iva , Mahler Michael , Svenungsson Elisabet , Rönnelid Johan
Published: June 2022

Objectives

Emerging evidence demonstrates that aPS-PT associate with thrombotic events. Genetic predisposition, including HLA-DRB1 alleles, is known to contribute to the occurrence of conventional aPL [anti-β2glycoprotein-I (anti-β2GPI) and aCL]. We investigated associations between aPS-PT and HLA-DRB1* alleles and thrombosis in SLE. Conventional aPL were included for comparison.

Methods

We included 341 consecutive SLE patients, with information on general cardiovascular risk factors, including blood lipids, LA and thrombotic events. aPS/PT, anti-β2GPI and aCL of IgA/G/M isotypes and LA were quantified.

Results

aPS/PT antibodies associated positively with HLA-DRB1*13 [odds ratio (OR) 2.7, P = 0.002], whereas anti-β2GPI and aCL antibodies associated primarily with HLA-DRB1*04 (OR 2.5, P = 0.0005). These associations remained after adjustment for age, gender and other HLA-DRB1* alleles. HLA-DRB1*13, but not DRB1*04, remained as an independent risk factor for thrombosis and APS after adjustment for aPL and cardiovascular risk factors. The association between DRB1*13 and thrombosis was mediated by aPS-PT positivity. HLA-DRB1*03, on the other hand, associated negatively with thrombotic events as well as all aPL using both uni- and multivariate analyses. HLA-DRB1*03 had a thrombo-protective effect in aPL-positive patients. Additionally, HLA-DRB1*03 was associated with a favourable lipid profile regarding high-density lipoprotein and triglycerides.

Conclusions

HLA-DRB1*13 confers risk for both aPS-PT and thrombotic events in lupus. The association between HLA-DRB1*13 and thrombosis is largely, but not totally, mediated through aPS-PT. HLA-DRB1*03 was negatively associated with aPL and positively with favourable lipid levels. Thus, HLA-DRB1*03 seems to identify a subgroup of SLE patients with reduced vascular risk.