bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A030 Secondary malignancies after radiotherapy treatment of pediatric cancer patients in Egypt over a six-year period
Authors: Sackett Charlotte L. , Zaghloul Mohamed S , Aldesouky Ahmed , Soliman Amr S , Teasdale Chloe A. 
Published: September 2024

Abstract
Background: Pediatric cancer survivors are at risk of developing secondary malignant neoplasms (SMNs) due to exposure to prior treatment modalities, including radiotherapy (RT). We conducted a retrospective cohort study to examine whether initial RT dose was associated with a greater risk of developing SMNs among pediatric cancer patients in Egypt. Methods: We identified patients (8 days-18 years at enrollment in care) who had received RT for treating primary cancer at Children’s Cancer Hospital (CCHE) in Cairo, Egypt, between 2009 and 2015. Patients were classified into two exposure groups based on the median initial RT course dosage, where ≤3600 centrigray (cGy) and &gt;3600 cGy were considered low and high RT exposure, respectively. The cumulative incidence of SMN accounting for the competing risk of death was compared by initial RT dose using the cumulative incidence function, and multivariable sub-distributional hazard (SHR) models were fitted to compare the hazards of SMN for children with low vs high initial RT dose. Results: Of the 3,132 patients included in this study, 60.1% were male and the median age at enrollment in care was 6.2 years (interquartile range: 3.5-10.7). Approximately half (50.6%) of the patients received a low initial RT dose. The cumulative incidence of SMN at 11.1 years was 3.05% (95% CI 1.15-5.93%) overall and 3.92% (95% CI 1.19-9.39%) and 2.01% (95% CI 0.77-4.38%) for low and high RT dose patients, respectively. Children who received high initial RT doses did not have higher hazards of developing SMN in bivariable (SHR 0.55, 95% CI 0.32-1.75) and multivariable models (aSHR 0.25, 95% CI 0.04-1.70). Conclusion: In this cohort of pediatric cancer patients in Egypt, high initial RT dose was not associated with increased hazards of SMN. Future research should extend follow-up time after the first decade following an initial cancer diagnosis to capture a more complete picture of SMN incidence. Other initiatives may include establishing national cancer registries in low- to middle-income countries to better track longitudinal cancer data in these populations.
Citation Format: Charlotte L. Sackett, Mohamed S Zaghloul, Ahmed Aldesouky, Amr S Soliman, Chloe A. Teasdale. Secondary malignancies after radiotherapy treatment of pediatric cancer patients in Egypt over a six-year period [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A030.
Abstract A038 Plasma exosome concentrations in healthy canines and dogs with osteosarcoma
Authors: Magstadt Jaron M. , Labé Courtney H. , Wojtysiak Meagan , DuVal Kyle , Khammanivong Ali , Mills Lauren J. , Winter Amber , Feiock Caitlin , Reid Kelly , Lewellen Mitzi , Spector Logan G. , Weigel Brenda J. , Modiano Jaime F. , Makielski Kelly M. 
Published: September 2024

Abstract
Canine osteosarcoma is a common disease that shares many clinical and biological features with human osteosarcoma. We have previously demonstrated the potential of using mRNA signatures derived from exosome cargo to detect minimal residual disease in dogs undergoing treatment for osteosarcoma. Our goal is to continue exploring the potential of exosomes in cancer diagnosis and treatment by understanding how exosomes contribute to the biology of osteosarcoma. For this study, we compared exosome concentrations in the plasma of 26 healthy dogs and 29 dogs with various cancers, including 8 dogs with osteosarcoma. Dogs with cancer had higher exosome concentrations than the healthy dogs (p=0.0007), as did the subset of dogs with osteosarcoma. Specifically, the average exosome concentration in the samples from healthy dogs was 5x1011 (+/-2.72x1011) particles/mL, with a normal distribution ranging from 7.22x1010 to 1x1012, whereas the average exosome concentration in the samples from dogs with osteosarcoma was 1.14x1012 (+/-1.41x1012) particles/mL, with a non-parametric distribution ranging from 1.16x1011 to 4.4x1012. Ongoing work includes expanding the data set with archival samples, as well as evaluating potential relationships between exosome concentrations and disease-free survival in dogs with osteosarcoma. In conclusion, the difference in plasma exosome concentrations between healthy dogs and dogs with osteosarcoma, and specifically the heterogeneous distribution of exosomes in the plasma of dogs with osteosarcoma suggests that this could be one feature used in combination with analyses of exosome cargo to aid in prognosis and manage treatment of patients with osteosarcoma.
Citation Format: Jaron M. Magstadt, Courtney H. Labé, Meagan Wojtysiak, Kyle DuVal, Ali Khammanivong, Lauren J. Mills, Amber Winter, Caitlin Feiock, Kelly Reid, Mitzi Lewellen, Logan G. Spector, Brenda J. Weigel, Jaime F. Modiano, Kelly M. Makielski. Plasma exosome concentrations in healthy canines and dogs with osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A038.
Abstract A047 Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma
Authors: Gupta Ajay , Connors Eoghan , Moser Michael , Gillard Bryan , Kokolus Katie , Basse Per , Kalinski Pawel 
Published: September 2024

Abstract
Introduction: Clinical effectiveness of immune checkpoint inhibitor (ICI) therapy depends on tumor-infiltrating cytotoxic T lymphocytes (CTLs) resulting in the need for new tools to convert “cold” tumors which lack CTLs, into CTL-infiltrated “hot” tumors. Radiation therapy (RT) is known to modulate the solid tumor microenvironment (TME) and induce a systemic immune response via enhanced tumor antigen release, production of type I interferons (IFN), intratumoral attraction and activation of DCs, and enhanced tumor recognition by natural killer (NK) cells. Thus, local irradiation of a tumor can be advantageous for both the local treatment of a tumor as well as the prevention of distant metastases. Since previous studies have shown that RT can synergize with ICI and that IL-12 producing DCs administered intratumorally also impart a clinical advantage with ICI, we tested if ST-αDC1s, a DC type designed to produce high levels of IL-12 and CTL-attracting chemokines, can enhance the combination of RT plus anti-PD-1 therapy of mouse rhabdomyosarcoma. Methods: Mice (10-15 mice per group) were inoculated with syngeneic orthotopic (gastrocnemius) M3-9-M rhabdomyosarcoma. At day 13, when tumors reached ∼200 mm3, animals started RT with single fraction of 6 Gy (225 peak kVp) using the Precision X-Rad 320 irradiator. Four doses of anti-PD-1 treatment were given on days 13, 15, 18, and 20. ST-αDC1s were given intratumorally either early (Day 13) or late (Day 20). Surviving animals were challenged with 2.5x higher number of cancer cells on day 90-100 and followed for evidence of tumor recurrence. Results: Anti-PD1 treatment alone was not effective. Control groups receiving PBS injection or anti-PD-1 alone had no survivors at day 90, with most animals succumbing to tumors within 4 weeks. RT alone improved the outcomes, yielding 15% of day-90 survivors (2/13 animals). RT plus anti-PD-1 treatment increased the fraction of survivors to 54% (7/13 animals) , while RT plus anti-PD-1 and early ST-αDC1 treatment resulted in 70% of survivors (7/10 animals). Late ST-αDC1 treatment did not enhance the survival beyond the RT plus anti-PD1 combination. The correlative studies and rechallenge studies will be presented.
Citation Format: Ajay Gupta, Eoghan Connors, Michael Moser, Bryan Gillard, Katie Kokolus, Per Basse, Pawel Kalinski. Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A047.
Abstract A057 Molecular iodine reduces the invasiveness of neuroblastoma xenografts in zebrafish
Authors: Juvera-Avalos Edgar R. , Orizaga-Osti Gustavo , Delgado-González Evangelina , Aceves Carmen 
Published: September 2024

Abstract
Neuroblastoma (NB) is one of childhood´s most common extra-cranial solid tumors, with 90 % of the cases occurring in those &lt;5 years of age. NB is highly heterogeneous, with variable biological and clinical characteristics; it exhibits spontaneous or induced regression processes (low-risk NB) up to highly invasive capacities and drug-resistance tumors (high-risk NB). High-risk NB overexpresses the N-MYC gene associated with invasion and chemoresistance. On the other hand, molecular iodine (I2) exerts antiproliferative and differentiation effects on cancer cells. Our previous studies have shown that I2 synergizes the neurodifferentiator effect of all-trans-retinoic acid in low-risk (SN-K-AS) and the antiproliferative and apoptotic action of cyclophosphamide in high-risk (SK-N-BE2) neuroblastoma cell lines. The cellular mechanisms include the activation of antioxidant pathways (Nrf2) and the overexpression of the peroxisome proliferator-activated receptor gamma (PPARγ). I2 can exert its effects through the activation of PPARγ, and this in turn downregulates the expression of chemoresistance genes (TrkB, MDR1, N-MYC). The aim of the present work is to analyze the effect of I2 on the invasive capacity of SK-N-BE2 both in vitro (wound healing assay) and in vivo (zebrafish model). NB cells were cultured in DMEM/F12 (1:1) medium with and without I2 400 mM for 96 hours. Wound assay was analyzed after 24 hours, whereas 400 to 600 cells labeled with Fast DiI (4 mg/mL) were injected into the perivitelline space of zebrafish larvae 2 days post fertilization. Cancer cell dissemination to the caudal vein plexus was analyzed with a fluorescence Nikon Eclipse E-600 microscope (10X/0.30 magnification) after 72 hours. Data show that I2-pretreated SK-N-BE2 cells exhibit a decrease in migration capacity in vitro (control 59.5 ± 8.5, I2 65.0± 9.4 p&lt;0.6) and a clear and significant inhibition in vivo (control 7.6 ± 4.6, I2 4.8± 3.8 p&lt; 0.0015). Analysis of the genetic expression (qRT-PCR) shows that I2 induces PPARγ and decreases N-MYC and TrkB expression through an apparent PPARγ independent pathway at 96 hours. The establishment of NB PPARγ knock-out cells and evaluation of the I2 effect in tumoral angiogenesis on transgenic zebrafish (Fli1: EGFP) is currently under progress. Acknowledgments The authors are grateful for the technical support of Luis Roberto Rodríguez Ortiz, Nydia Hernandez Ríos, and Martín García Servín. This work was supported by PAPIIT-UNAM IN202322, and CONAHCYT scholarship 862245.
Citation Format: Edgar R. Juvera-Avalos, Gustavo Orizaga-Osti, Evangelina Delgado-González, Carmen Aceves. Molecular iodine reduces the invasiveness of neuroblastoma xenografts in zebrafish [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A057.
Abstract A060 Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas
Authors: Walker-Mimms Hannah L. , Londono Nicole , Liao Yi , Chaudhary Neelkamal , Teng Mingxiang , Kinose Fumi , Li Xueli , Monastyrskyi Andrii , Rix Uwe , Duckett Derek 
Published: September 2024

Abstract
Ewing (ES) and clear cell (CCS) sarcomas are bone and soft tissue malignances and in advanced and relapsed disease overall survival rates remain dismal. For metastatic ES, five-year survival rates are between 15% and 30%. In CCS, the five-year survival rates are between 30% and 67%. Accordingly, there is a critical need for the development of novel targeted therapeutics for the treatment of these rare cancers. Both cancers are driven by fusion proteins; EWS-FLI1 in ES and EWS-ATF1 in CCS, which arise from separate chromosomal translocations: t(11;22)(q24;q12) and t(12;22)(q13;q12) respectively. Current approaches for developing new treatments focus on targeting the fusion proteins or their downstream targets. We performed a small molecule compound library screen of clinically used drugs and identified ES and CCS cells to be extremely sensitive to filanesib, a kinesin spindle protein (KIF11) inhibitor. KIF11 is known to play roles in cell cycle progression and mitotic spindle stability. Our preclinical efficacy studies demonstrated that filanesib promotes potent tumor growth inhibition in both EWS-FLI1 and EWS-ATF1 xenograft models in mice. We are currently investigating the mechanism underlying the relationship between KIF11 and EWS-FLI1 and EWS-ATF1. Prior studies have identified KIF11 within a EWS-ATF1 transcriptional complex and KIF11 has been shown to interact with the histone acetyltransferase (HAT) p300/CBP-Associated Factor (PCAF). HATs are necessary components for chromatin remodeling, which the oncogenic fusion proteins regulate. Future research directions involve elucidating the role of KIF11 in regulating the EWS-ATF1 and EWS-FlI1 transcriptional complexes. Additionally, to further improve the therapeutic response to filanesib, we are investigating potential synergistic relationships with other compounds. This work has been supported in part by the Flow Cytometry and the Molecular Genomics Cores at the H. Lee Moffitt Cancer Center & Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by Moffitt’s Cancer Center Support Grant (P30-CA076292)
Citation Format: Hannah L. Walker-Mimms, Nicole Londono, Yi Liao, Neelkamal Chaudhary, Mingxiang Teng, Fumi Kinose, Xueli Li, Andrii Monastyrskyi, Uwe Rix, Derek Duckett. Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A060.
Abstract A071 Mechanisms of radiation resistance in medulloblastoma
Authors: Veo Bethany , Wang Dong , Desisto John , Vibhakar Rajeev 
Published: September 2024

Abstract
Medulloblastoma (MB) is the most prevalent malignant brain tumor in children that demonstrates clinical and genomic heterogeneity. Of the four major subgroups, Group 3 tumors (MYC-MB), and particularly the 3gsubtype, exhibit high levels of MYC, high rates of metastasis, and have the worst prognosis. Despite treatment with surgery, radiation and chemotherapy, Group 3 medulloblastoma patients are more likely to develop recurrent tumors which are far more aggressive resulting in a 5-year survival rate after recurrence of 12%. Thus, there is an imperative need to examine the underlying mechanisms mediating treatment resistance. Recent evidence has identified cellular plasticity, as a major driver of therapy resistance. To investigate whether epigenetic mediated cell plasticity contributes to Myc-MB therapy response we performed Single Nuclei Multiome ATAC + Gene Expression analysis of paired primary and relapsed tumors. We identified the emergence of novel progenitor populations in resistant tumors with stem-like gene expression networks and altered chromatin accessibility. These emergent popuoations demostrated new enhancer-promoer interactions and exhibited increased metabolic reprogramming with potential for theraputic targeting. Because radiation is one of the key treatment modalities for Myc-MB, we chose to model radiation resistance in further studies. Single-cell RNA sequencing of outgrown in vivo irradiated orthotopic xenograft MB tumors showed an overall upregulation of metabolic pathways with the enhancement of genes that mediate oxidative phosphorylation and glutamate metabolism centering on wild-type IDH1 (wtIDH1), consistent with our patient data. IR-resistant cells showed altered chromatin occupancy of H3K3me3 and H3K27Ac. Disruption of IDH1 activity in IR resistant cells in vitro altered the epigenomic landscape, facilitating reversion to the pre-irradiated state. Interestingly, we observed that pluripotent genes with bivalent regions (H3K4me3 and H3K27me3) were enhanced in radiation-resistant cells and suppressed by IDH1 inhibition. Metabolic mass spectrometry reveled that metabolites from the citric acid cycle and synthesis of unsaturated fatty acids were among the main metabolically elevated molecules in radiation-resistant cells consistnat with the observed epigenomic reprograming. IDH1 inhibition reversed the metabolic reprograming and resensitized MB cells to radiation. In total our data identify a novel mechanism of radiation resistance in medulloblastoma with potential theraputic implications.
Citation Format: Bethany Veo, Dong Wang, John Desisto, Rajeev Vibhakar. Mechanisms of radiation resistance in medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A071.
Abstract B016: Unravelling personalized drug vulnerabilities in pediatric solid tumors—functional precision medicine approach
Authors: Kuusela Sara , Martikainen Enni , Eloranta Katja , Wang Wenyu , Kumari Romika , Potdar Swapnil , Dashi Giovanna , Lohi Jouko , Mutka Aino , Tynninen Olli , Kanerva Jukka , Pentikäinen Virve , Koskenvuo Minna , Pietiäinen Vilja M. 
Published: September 2024

Abstract
Many pediatric cancer patients with high-risk primary, refractory, or relapsed tumors still lack effective treatment strategies and frequently suffer from both acute and delayed adverse drug effects, including secondary cancers. These tumors are generally characterized by very few druggable molecular alterations, diminishing the advantage of genetics in defining patient-specific treatments. The purpose of this study is to utilize the functional precision medicine approach to provide improved diagnostics and better therapy options for pediatric solid tumors through deep molecular and functional profiling in a patient-specific manner. Here, we describe the results of our current study, which includes exome sequencing for germline and somatic mutations, and transcriptomics analysis for fusion genes, as well as ex vivo drug testing of patient-derived cancer cells (PDCs) in real-time clinical set-up. Our current clinical data and sample collection, currently from 40 patients, include different types of pediatric solid tumors, such as central nervous system (CNS) tumors, sarcomas, and neuroblastomas. We have prepared PDC cultures and screened them using a 3D-drug sensitivity and resistance testing (DSRT) platform with an internationally defined pediatric solid tumor drug panel. Our results include the drug testing results of control cell lines and primary healthy cells to assess the general cytotoxicity of the drugs and patient-specific responses. We present our "fast-track" functional precision medicine concept, incorporated as part of biobank operations to return clinically relevant findings back to the treating clinicians, and exemplify the data returned to the clinics as well as its potential clinical impact. In conclusion, our findings demonstrate that the functional precision medicine approach can i) help to discover clinically relevant molecular events important for diagnosis and treatment, and ii) increase our biological understanding of drug vulnerabilities in pediatric cancers.
Citation Format: Sara Kuusela, Enni Martikainen, Katja Eloranta, Wenyu Wang, Romika Kumari, Swapnil Potdar, Giovanna Dashi, Jouko Lohi, Aino Mutka, Olli Tynninen, Jukka Kanerva, Virve Pentikäinen, Minna Koskenvuo, Vilja M. Pietiäinen. Unravelling personalized drug vulnerabilities in pediatric solid tumors—functional precision medicine approach [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B016.
Abstract B017: Aberrant translation of microproteins as a source of new cancer dependencies in medulloblastoma
Authors: Prensner John , Bandopadhayay Pratiti , Saha Soumik , Lupien Leslie , Choi Seung H. 
Published: September 2024

Abstract
A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation.Dysregulation of ribosome activity not only influences known protein-coding genes, but also unannotated small open reading frames (sORFs) as well.We have recently shown that sORFs may produce functional microproteins in medulloblastoma.Here, we performed an integrative analysis of medulloblastoma patient samples and cell lines.We used ribosome profiling, RNAseq, and mass spectrometry to delineate dysregulation of microprotein production.We employed cell models of MYC overexpression to determine the role of MYC in selective translation of microproteins in medulloblastoma, finding specific associations with upstream open reading frames (uORFs) located in gene leader sequences.We then designed a step-wise approach to define functional microproteins in medulloblastoma through the use of CRISPR/Cas9 screens, saturation mutagenesis, and base editing.We observed distinctive signatures of microprotein bioactivity based on the molecular drivers of medulloblastoma according to disease subtypes.In the Group 3 subtype, we observed an enrichment for bioactive uORFs relative to other disease settings.We then characterized several key microprotein dependencies resulting from uORFs including a molecular mechanism for one candidate, ASNSD1-uORF, in mediating protein-RNA dyssynchrony in Group 3 medulloblastoma.Protein-RNA dyssynchrony is the divergent regulation of protein abundance from RNA abundance, and is a hallmark of Group 3 medulloblastoma.We probed the clinical and therapeutic implications of protein-RNA dyssynchrony and determined that this process may be associated with patterns of drug sensitivity and resistance in medulloblastoma.With this insight, we have now used ASNSD1-uORF to stratify medulloblastoma resistance patterns to inhibitors of RNA transcription.We determine that an interplay between RNA translational control and RNA transcriptional control, while driving resistance in some settings, may also reveal additional drug targets, such as cyclin-dependent kinases.Our findings underscore the fundamental importance of sORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets and therapeutic insights.
Citation Format: John Prensner, Pratiti Bandopadhayay, Soumik Saha, Leslie Lupien, Seung H. Choi. Aberrant translation of microproteins as a source of new cancer dependencies in medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B017.