bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODL-04. ZEBRAFISH: THE FUTURE OF PEDIATRIC BRAIN CANCER RESEARCH
Authors: Roy Debasish , Subramaniam Bavani , Chong Wai Chin , Nazarian Javad 
Published: June 2024

Abstract
Pediatric brain cancers cause the highest rate of mortality amongst all childhood cancers. Most high-grade gliomas are difficult to treat mainly due to impermeability across the blood-brain barrier, or systemic toxicity. Here, we explore the benefits of zebrafish to assess drug toxicity, orthotopic pediatric brain cancer model development and drug screening. We assessed the toxicity of eight anti-cancer drugs with diverse mechanisms of action. In addition to the survival assay (LC50), we analyzed other teratogenic characteristics to demonstrate the detrimental developmental toxicity, which was critical in determining drug safety for future human usage. To develop fast and reproducible orthotopically xenografted pediatric brain cancer models, we injected approximately 80-100 mCherry expressing JHH-NF1-PA1 and TM-31 cells into the midbrain of 2 days post-fertilization (dpf) zebrafish embryos and imaged daily for next 4 days to monitor the survival, progression, and invasion of the injected cells. Our results show that both cell types were engrafted successfully and multiplied inside the developing zebrafish brain. As compared to JHH-NF1-PA1 cells, which mostly migrated caudally within the developing spinal cord, TM-31 migrated in multiple directions and metastasized five times more rapidly. To check the efficiency of VAL-083 and AZD-1775 in high-grade glioma, 2 dpf zebrafish embryos were injected with mCherry expressing HGG cells, SF8628. At one day post-injection (dpi), the xenografted embryos were exposed to different combinations of Val-083 and AZD-1775 for 72 hours. After 4 dpi, tumor cell invasion and migration in zebrafish were quantified. We found that the combination group had the lowest tumor burden with significantly lower fluorescence intensity, total area of migration, and reduced number of metastatic cells (p&lt;0.001) compared to single or no drug treatment groups. Our study showed that zebrafish is a valuable, rapid, and cost-effective in-vivo pediatric brain cancer pre-clinical model to assess tumor proliferation, metastasis, and rapid drug screening.
MODL-05. UNDERSTANDING THE METABOLIC VULNERABILITIES IN INFILTRATING GLIOMATOSIS CEREBRI CELLS
Authors: Bahadoor Hriday , Salmanli Chinar , Outlifah Hassiba , Hubsch Clemence , Deschuyter Marlène , Namer Izzie Jacques , Reita Damien , Martin Sophie , Dontenwill Monique , Entz-Werle Natacha 
Published: June 2024

Abstract

BACKGROUND
Gliomatosis cerebri (GC), a rare form of high-grade glioma, is characterized by a particularly invasive phenotype within multiple lobes of the brain and a dismal prognosis. This entity was removed in 2016 of the WHO brain tumor classification because of an absence of specific GC driving molecular signature. Its diffusive aspect on MRI is defined by an absence of cohesive tumor mass, a mild contrast enhancement and a rare neoangiogenesis. Based on those observations, our objectives were to understand how these cells are adapting to their brain environment without a physiological nutritive efflux associated to a reduced oxygen concentration and determine a metabolic signature of GC.

METHODS
Preliminary results in a large cohort of HGGs bearing several drivers (H3.3 G34V, NMYC amplified, BCOR positive) or a more “wildtype” phenotype with new entities (pedRTK 1 and 2) were underlining glucose and glutamine as major nutrients in cell metabolic suppliance. Therefore, epigenetic assessments, bulk metabolomics, and Seahorse technology, as well as labeled glucose and glutamine metabolites study, helped us in pediatric GC-derived cell lines (BT97 and BT139, PEDIAMODECAN program) to understand the role of both nutrients and their central role in GC in hypoxic microenvironment.

RESULTS
Both glucose and glutamine are involved in carbon fueling biosynthesis in those cells. Glutamine is much more involved in supplying nitrogen to fuel several specific amino acids and mitochondrial metabolisms. Meanwhile, we developed drug testing using Matrigel invasion aspects. The tested drugs were able to reduce invasiveness of GC cells and modify the intratumoral metabolism.

CONCLUSION
All those observations seem to explain GC cell adaptation into the hypoxic microenvironment, their plasticity and resistance through metabolic reprogramming based on glutaminolysis and glycolysis.
MODL-06. USING HYDROGEL MODELS TO RECAPITULATE THE TUMOUR-IMMUNE MICROENVIRONMENT OF AGGRESSIVE GROUP 4 MEDULLOBLASTOMA TUMOURS
Authors: Forder-Denham Isabelle , Kerr Ian , Jackson Andrew M , Coyle Beth 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common malignant childhood brain-tumour, predominantly affecting children between the ages of one and nine. It is divided into four molecular subgroups amongst which, Group 3 (G3) and Group 4 (G4) subgroups have the worst prognosis. Subgroups possess distinct extracellular-matrix (ECM) and tumour immune microenvironments (TIME) directly influencing therapy-response and metastasis. Current models of medulloblastoma fail to precisely recreate the complex, subgroup-specific TIME and do not mimic intricate immune-tumour heterotypic signalling facilitating immune-evasion. Here we use a HyStem-hydrogel which forms a hyaluronan-rich environment mimicking the natural brain architecture. This overcomes several limitations of current MB models, allowing customisation of subgroup matching of ECM components, adjustable ECM-stiffness and co-culturing of immune cells.

METHODS
HyStem-hydrogels were co-assembled with ECM components (with/without laminin) and G4 medulloblastoma cell line CHLA-01-MED. Hydrogels were imaged every three-days using an EVOS M7000 system and assessed for cell-viability with PrestoBlue every seven days. Co-culture laminin-supplemented HyStem hydrogels were established with M1-like or M2-like resting/activated macrophages and their growth tracked in the same manner. On day twenty-eight, hydrogels were fixed and stained for markers of cellular proliferation (Ki-67), ECM (laminin, vitronectin) and macrophage markers. Media from hydrogel co-cultures was collected and ELISAs permofmed to assess cytokine production.

RESULTS
Hydrogels with/without laminin both remained viable and stable for 28 days. Laminin-supplemented hydrogels displayed a mixed laminar-nodular phenotype which mirrored the heterogenous nature of G4 patient-tumours. Co-culture of CHLA-01-MED cells with activated-macrophages led to cytokine production and altered growth patterns.

CONCLUSION
We show that HyStem hydrogels recapitulate biologically relevant behaviour of aggressive G4-MB tumours in vitro and represent a promising model for G4-tumours. Future research will involve inclusion of additional brain relevant cells/ECM components and comparisons to a fully customisable peptide-amphiphile hydrogel.
MODL-09. IMAGE-BASED SCREENING IN MEDULLOBLASTOMA REVEALS TUMOR-SUPPRESSIVE EFFECTS OF THE NEUROPROTECTIVE AGENT URMC-12K
Authors: Yan Shen , Ciraulo Bernard , Jovanovic Dejana , Hochuli Dina , Alvarez Veronica Akle , Özalp Özgün , Neuhauss Stephan C F , Allalou Amin , Baumgartner Martin 
Published: June 2024

Abstract

BACKGROUND
Enhanced motility and the invasive behavior of medulloblastoma (MB) influence microenvironment interactions and may promote distant spread. Current drug screening focuses on cytotoxic agents, leaving subtle but potentially therapeutically relevant drug phenotypes associated with motility and invasiveness unrecognized. The serine/threonine kinase MAP4K4 is upregulated in MB and promotes invasiveness1,2. Toxicities associated with existing MAP4K4 inhibitors in the CNS prevented further pre-clinical evaluation. URMC-12k is a novel MAP4K inhibitor identified as a motor-neuron-protective agent in ALS. Using advanced imaging approaches, we investigated URMC-12k as a tumor-suppressive drug in MB and characterized its effects at the molecular, cellular, and tissue levels.

METHODS
We use cell-based 3D invasion assays and quantitative microscopy to assess tumor-restraining activities of URMC-12k, and machine learning to detect URMC-12k phenotypes associated with repressed motility. We use tissue and zebrafish larval models to explore URMC-12k effects on cell and tissue viability and anti-invasion efficacy. We determined URMC-12k targets in MB cells using phosphoproteomics.

RESULTS
URMC-12k outcompetes existing MAP4K4 inhibitors in repressing basal and growth-factor-induced matrix invasion with no detectable effects on vertebrate developmental processes. A computational model trained to detect morphological alterations in the actin cytoskeleton associated with cell dynamics established a firm correlation between the URMC-12k-repressed motile behavior and alterations in the tumor cell actin cytoskeleton. Quantitative imaging further revealed that URMC-12k promoted increased cell clustering and reduced deposition of extracellular vesicles. Phosphoproteomics identified proteins involved in cell adhesion organization and vesicle trafficking as potential molecular effectors targeted by URMC-12k.

CONCLUSIONS
URMC-12k effectively inhibits MB cell migration and displays no toxicities at effective concentrations. The regulation of cell-cell adhesion molecules and the deposition of extracellular vesicles revealed by URMC-12k are tumor-promoting, druggable mechanisms of MAP4Ks in MB. 1. 1Migliavacca, J., et al. Commun Biol5, (2022). 2. 2Tripolitsioti, D. et al. Oncotarget9, 23220–23236 (2018).
MODL-12. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO SENSITIZE DMG TO CDK9 INHIBITORS
Authors: Murdaugh Rebecca L , Eberl Brittany R , Richard Rosemary U , Tremblay Jack R , Dei-Ampeh Alfred , Olson Calla M , Anastas Jamie N 
Published: June 2024

Abstract

BACKGROUND
Diffuse Midline Glioma (DMG) comprise a subset of aggressive pediatric brain tumors with few effective therapies. Cyclin-dependent kinase 9 inhibitors (CDK9i) like zotiraciclib (ZTR) are in clinical trials for adult and pediatric glioma, but resistance frequently develops. In this study, we find that co-treatment with CDK9i and brain penetrant, FDA-approved drugs targeting neurotransmitter signaling alters DMG transcription and reduces DMG growth and tumorigenesis.

METHODS
We conducted drug screens to assess DMG response to a sub-threshold dose of ZTR combined with a library of ~220 bioactive and FDA-approved compounds. Combinatorial effects of CDK9i+SSRI/SNRI treatment were confirmed through in vitro dose curve studies and in orthotopic DMG xenograft models. We identified downstream targets of CDK9i+SSRI/SNRI treatment through phospho-proteomic profiling, RNAseq analysis, immunofluorescence staining, and Western blotting.

RESULTS
Our targeted drug screens identified SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors) that increase DMG sensitivity to a low dose of zotiraciclib (ZTR). Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres, induce the apoptotic marker cleaved caspase 3, and reduce the expression of proliferation markers. Additional proteogenomic analyses define downstream targets of CDK9i+SSRI co-treatment, including differential phosphorylation of chromatin regulators and RNA Polymerase 2 (Pol2)-associated elongation factors and splicing machinery. Further RNAseq studies reveal robust transcriptional changes induced by CDK9i+SSRI treatment characterized by altered expression of developmental and synaptic signaling genes. Finally, pilot pre-clinical studies find that CDK9i+SSRI treatment reduces tumor growth and increases progression free survival in a DMG xenograft model.

CONCLUSIONS
We have identified synergistic CDK9i+SSRI drug combinations that can be applied to alter malignant gene regulation and reduce DMG growth in vitro and in xenografts. These studies provide a basis for a drug-repurposing strategy to combine SSRI/SNRI and CDK9 inhibitors for DMG treatment.
RADT-04. ASSESSMENT OF CLINICAL AND NEUROLOGICAL ALTERATIONS BEFORE RADIATION THERAPY IN CHILDREN WITH MALIGNANT BRAIN TUMORS
Authors: Lecchi Mara , Erbetta Alessandra , Cavatorta Claudia , Nigro Olga , Oprandi Chiara Maria , Pecori Emilia , Biassoni Veronica , Schiavello Elisabetta , Grampa Paolo , Meroni Silvia , Nigri Anna , Peruzzo Denis , Alessandro Ombretta , Laureanti Rita , Mainardi Luca , Vennarini Sabina , Poggi Geraldina , Pignoli Emanuele , Verderio Paolo , Massimino Maura 
Published: June 2024

Abstract

BACKGROUND
Young patients with malignant brain tumors show neurocognitive alterations as both consequences of the tumor and of treatments received. A prospective study of longitudinal radiation damages after focal RT was activated in 2017. We present the first analysis correlating tumor localization, symptoms, neurological/endocrinological impairments, surgery/ies if adopted, and cognitive assessments at the time of enrollment.

METHODS
Sixty-six children eligible for focal RT were enrolled and underwent a neurocognitive assessment based on standardized tests (“impaired”/“non-impaired”). The database included demographical, clinical and pathological variables. The latter, together with MRI morphological scans, were used to define different kind of damage scores. The pattern of associations between clinical variables and damage scores was investigated.

RESULTS
Patients median age was 8 years; the most frequent tumor was Ependymoma (41%) and Posterior Fossa (29%) was the prevalent tumor site. All but 5 children (with Germ Cell Tumors), had undergone surgery and 32 had undergone chemotherapy before irradiation and evaluations. Ad-hoc scores of neurological deficits and endocrine alterations were created to characterize each patient. Moreover, structural abnormalities were quantified in a score for each cortical/subcortical region. Patients with posterior fossa Ependymomas and infratentorial tumors showed higher neurological damage scores. Endocrine alterations were more serious in supratentorial tumors, specifically in patients with Craniopharyngioma and Germ Cell tumors of the sellar region and ventricular system. Deficit scores were not associated to the presence of hydrocephalus and surgery, unlike endocrine alteration scores. The median number of child’s structural damaged areas was equal to 2 (IQR: 2-3). Tumor sites of patients with an impaired or non-impaired full-scale IQ or visual-perception index, was found to be different.

CONCLUSIONS
The analysis of baseline evaluations highlights damages preexisting to irradiations and generated by multiple factors. In light of these findings, damages over time could be better investigated by distinguishing multiple generating factors.
Meeting the Therapeutic Challenges of Emergent and Rare Invasive Fungal Diseases Through Novel Clinical Trial Designs
Authors: Walsh Thomas J 
Published: June 2024

Abstract
Treatments for emerging and rare invasive fungal diseases (IFDs) represent a critical unmet medical need. For IFDs that occur less frequently than invasive aspergillosis, such as mucormycosis, hyalohyphomycosis, and phaeohyphomycosis, randomized controlled clinical trials are impractical and unlikely to meet urgent public health needs. Understanding regulatory approaches for approval of drugs for rare cancers and rare metabolic diseases could help meet the challenges of studying drugs for rare IFDs. A single-arm, controlled clinical trial with a high-quality external control(s), with confirmatory evidence from nonclinical studies, including pharmacokinetic/pharmacodynamic data in predictive animal models of the disease may support findings of effectiveness of new drugs and biologics. Control populations may include historical controls from published literature, patient registries, and/or contemporaneous external control groups. Continuous engagement among clinicians, industrial sponsors, and regulatory agencies to develop consensus on trial design and innovative development pathways for emergent and rare invasive fungal diseases is important.
A Multimodal Approach to Measuring Listening Effort: A Systematic Review on the Effects of Auditory Task Demand on Physiological Measures and Their Relationship
Authors: Keur-Huizinga Laura , Kramer Sophia E. , de Geus Eco J. C. , Zekveld Adriana A. 
Published: June 2024

Objectives:
Listening effort involves the mental effort required to perceive an auditory stimulus, for example in noisy environments. Prolonged increased listening effort, for example due to impaired hearing ability, may increase risk of health complications. It is therefore important to identify valid and sensitive measures of listening effort. Physiological measures have been shown to be sensitive to auditory task demand manipulations and are considered to reflect changes in listening effort. Such measures include pupil dilation, alpha power, skin conductance level, and heart rate variability. The aim of the current systematic review was to provide an overview of studies to listening effort that used multiple physiological measures. The two main questions were: (1) what is the effect of changes in auditory task demand on simultaneously acquired physiological measures from various modalities? and (2) what is the relationship between the responses in these physiological measures?

Design:
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, relevant articles were sought in PubMed, PsycInfo, and Web of Science and by examining the references of included articles. Search iterations with different combinations of psychophysiological measures were performed in conjunction with listening effort-related search terms. Quality was assessed using the Appraisal Tool for Cross-Sectional Studies.

Results:
A total of 297 articles were identified from three databases, of which 27 were included. One additional article was identified from reference lists. Of the total 28 included articles, 16 included an analysis regarding the relationship between the physiological measures. The overall quality of the included studies was reasonable.

Conclusions:
The included studies showed that most of the physiological measures either show no effect to auditory task demand manipulations or a consistent effect in the expected direction. For example, pupil dilation increased, pre-ejection period decreased, and skin conductance level increased with increasing auditory task demand. Most of the relationships between the responses of these physiological measures were nonsignificant or weak. The physiological measures varied in their sensitivity to auditory task demand manipulations. One of the identified knowledge gaps was that the included studies mostly used tasks with high-performance levels, resulting in an underrepresentation of the physiological changes at lower performance levels. This makes it difficult to capture how the physiological responses behave across the full psychometric curve. Our results support the Framework for Understanding Effortful Listening and the need for a multimodal approach to listening effort. We furthermore discuss focus points for future studies.
Spine Involvement and Vertebral Deformity in Patients Diagnosed with Chronic Recurrent Multifocal Osteomyelitis
Authors: Rogers Nathan D. , Trizno Anastasiya A. , Joyce Christopher D. , Roberts Jesse L. , Soep Jennifer B. , Donaldson Nathan J. 
Published: June 2024

Background:
Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder of bone, typically arising adjacent to the physes of long bones but also seen throughout the skeleton. For patients with spinal involvement, CRMO lesions can cause compression deformities with a range of severity from minimal anterior wedging to circumferential height loss, known as vertebra plana. This study examines a large cohort of CRMO patients to determine the prevalence of spine involvement and vertebral deformity.

Methods:
This is a retrospective review of all patients with a diagnosis of CRMO seen at our institution between January 2003 and December 2020. These patients were identified through a prospectively maintained database of all CRMO patients seen at the institution. A retrospective review was undertaken to identify all patients with spinal involvement and determine the prevalence of CRMO in the spine and its effects on vertebral height and deformity.

Results:
Of 170 patients included in this study, 48 (28.2%) were found to have spinal involvement. Among patients with spinal involvement, vertebral body lesions were identified in 27 (56.3%) patients. The remaining lesions were in the sacrum or posterior elements. Radiographic evidence of the vertebral body height loss was noted in 23 of these 27 patients.

Conclusions:
This cohort of CRMO patients demonstrates that 28% of patients have spinal involvement, and 48% of those patients have vertebral body height loss. While the ideal treatment for spinal CRMO has yet to be determined, imaging studies, including whole-body MRI and spine-specific MRI, are useful in identifying vertebral lesions and deformities. Identification and surveillance of these lesions are important as the disorder has a relapsing and remitting course, and patients can develop significant vertebral body height loss. Once deformity has developed, we have seen no evidence of reconstitution of the height of the collapsed vertebra. Bisphosphonates have been successful in preventing the progression of vertebral body height loss.

Level of Evidence:
Level II: Retrospective study investigating spinal involvement and prevalence of vertebral body deformity in patients diagnosed with CRMO.
The Piggyback Superficial Circumflex Iliac Perforator Flap for Complex Free Flap Reconstructions
Authors: Yoshimatsu Hidehiko , Nakatsuka Kengo , Karakawa Ryo , Fuse Yuma , Yano Tomoyuki 
Published: June 2024

Summary:
This article introduces a reproducible strategy for complex reconstruction scenarios that require the use of two flaps. It specifically focuses on the utilization of the superficial circumflex iliac artery perforator (SCIP) flap as a secondary flap, particularly in complex cases where available arterial options are limited. In the first scenario, the SCIP flap is elevated simultaneously during elevation of a fibula bone flap. The pedicle of the fibula flap will be anastomosed to the recipient vessels, and the pedicle artery of the SCIP flap, the superficial circumflex iliac artery, will be anastomosed to the distal end of the peroneal artery. The SCIP flap pedicle offers greater length compared with a cutaneous flap sourced from the peroneal artery, thus providing increased flexibility for the flap inset. In the second scenario, the SCIP flap is combined with the anterolateral thigh (ALT) flap to manage a significant defect. The pedicle of the ALT flap is anastomosed to the recipient vessels, and the superficial circumflex iliac artery is anastomosed to the distal end of the pedicle artery of the ALT flap, the descending branch of the lateral circumflex femoral artery. The SCIP flap can be harvested simultaneously with a fibula flap or an ALT flap from the same side, and its arterial anastomosis can always be established with the distal ends of the arterial pedicle of these two flaps. This efficient and reproducible method can also contribute to minimal donor site morbidity and will be particularly valuable in settings where recipient artery choices are limited.